CN108997183B

CN108997183B - Difluoromethylation reagent and preparation method and application thereof

Info

Publication number: CN108997183B
Application number: CN201811022609.3A
Authority: CN
Inventors: 刘国凯; 陆声乐; 李鑫; 秦文兵
Original assignee: Shenzhen University
Current assignee: Shenzhen University
Priority date: 2018-09-03
Filing date: 2018-09-03
Publication date: 2020-02-07
Anticipated expiration: 2038-09-03
Also published as: CN108997183A; WO2020047985A1

Abstract

The invention belongs to the technical field of chemical preparation, and particularly relates to a difluoromethylation reagent and preparation and application thereof. Aiming at the key problem that the stability of the electrophilic difluoromethylation reagent is poor at present, the problem of the stability of the reagent is solved through innovative design. Synthesizing to obtain an electrophilic difluoromethylation reagent which is stably preserved at room temperature; can meet the difluoromethyl functionalization of different types of substrates, and develop a plurality of new difluoromethylation methods and new reactions. And the reagent is solid, the use and the operation are simple and convenient, and the operability is high.

Description

Difluoromethylation reagent and preparation method and application thereof

Technical Field

The invention belongs to the technical field of chemical preparation, and particularly relates to a difluoromethylation reagent and a preparation method and application thereof.

Background

Difluoromethyl is an important fluoroalkyl group, and due to the high electronegativity of fluorine, protons in difluoromethyl have strong acidity, so that intramolecular or intermolecular hydrogen bonds are easily formed. The introduction of difluoromethyl groups into organic molecules often brings about changes in specific physical, chemical and biological properties. Due to the characteristics and advantages of difluoromethyl, the difluoromethyl group can be widely applied to the fields of medicines, pesticides, advanced functional materials, life sciences and the like.

For example, the references:

a)、Smart,B.E.Chem.Rev.1996,96,1555g)T.Furuya,C.Kuttruff,T.Ritter,Curr.Opin.DrugDiscoveryDev.2008,11,803；

b)、M.Bassetto,S.Ferla,F.Pertusati,FutureMed.Chem.2015,7,527；

c)、NewFluorinatedCarbons:FundamentalsandApplications(Eds.:O.V.Boltalina,T.Nakajima),Elsevier,Amsterdam,2016；

d)、K.Müller,C.Faeh,F.Diederich,Science2007,317,1881；e)J.Hu,W.Zhang,F.Wang,Chem.Commun.2009,7465。

especially, the method plays an important role in the design, discovery and development of drug molecules. Difluoromethyl compounds, widely used in drug development, difluoromethyl (CF)₂H) Is a bioisostere of hydroxyl (OH), Sulfhydryl (SH) and other groups.

For example, the references:

a)、G.K.S.Prakash,M.Mandal,S.Schweizer,N.A.Petasis,G.A.Olah,J.Org.Chem.2002,67,3718-3723；

b)、F.Narjes,K.F.Koehler,U.K℃h,B.Gerlach,S.Colarusso,C.Steink_hler,M.Brunetti,S.Altamura,R.DeFrancesco,V.G.Matassa,Bioorg.Med.Chem.Lett.2002,12,701-704.。

in addition, as an important factor influencing the pharmacological activity and the affinity with a target point of a drug, the hydrogen bonding action between a drug molecule and a target protein plays an important role. And as a hydrogen bond donor, difluoromethyl (CF)₂H) Compared with hydroxyl (OH), amino (NH) and the like, the compound has better lipophilicity, and can improve the lipid solubility, membrane permeability, bioavailability, other pharmacokinetic properties and the like of drug molecules.

For example, the references:

a)、Y.Li,J.Hu,Angew.Chem.Int.Ed.2005,44,5882-5886；b)G.K.S.Prakash,C.Weber,S.Chacko,G.A.Olah,Org.Lett.2007,9,1863-1866。

the stable and efficient difluoromethyl reagent and the corresponding difluoromethylation method are developed, difluoromethyl is selectively introduced into drug molecules, the research on the mutual relation between the structure and the property of the drug is facilitated, a new lead compound with special properties is discovered, and the development of a new drug is accelerated. Therefore, the introduction of difluoromethyl plays an important role in drug design and new drug creation. Therefore, the research and development of a novel electrophilic difluoromethyl reagent with high efficiency and stability, a novel difluoromethyl method under corresponding mild conditions and the development of a novel reaction have high application value, wide prospect and higher academic significance. The drug containing difluoromethyl group is shown in figure 1.

However, as the most important strategy and approach for directly introducing difluoromethyl group into organic molecules, especially in the late stage of total synthesis of drug molecules, regionally, stereoselectively and selectively, the development of non-functionalized direct electrophilic difluoromethyl reagent and its application has met with great difficulty, so far, the research results of stable and effective electrophilic difluoromethyl reagent and corresponding difluoromethylation method have been reported, and only difluoromethyl sulfonium salt and N, N-dimethyl protected sulfoximine developed by Prakash et al in the last 20 years, such as reference:

a)、G.K.S.Prakash,C.Weber,S.Chacko,G.A.Olah,Org.Lett.2007,9,1863-1866.

b)、G.K.S.Prakash,Z.Zhang,F.Wang,C.Ni,G.A.Olah,J.FluorineChem.2011,132,792-798.

and N-p-toluenesulfonyl protected difluoromethyl sulfoximine reagent developed by kumquat et al, for example references:

a)、W.Zhang,F.Wang,J.Hu,Org.Lett.2009,11,2109-2112.)

and more recently developed electrophilic difluoromethyl reagents of the sulfoylide type, such as references:

a)、J.Zhu,Y.Liu,andQ.Shen,Angew.Chem.Int.Ed.2016,55,9050-9054.，

b) shen Qi Long, Zhu Jiang Sheng, Liu ya Fei, CN107235878A,

however, difluoromethyl sulfonium salt is mainly used for difluoromethylation reaction of heteroatom nucleophiles such as N, P, S, O due to problems in reagent stability, reaction activity and the like, and has low efficiency and limited substrate type and functional group compatibility, and the application of difluoromethylation efficiency of important C nucleophiles is greatly limited. Moreover, the reagent is viscous semisolid, has poor operability and is inconvenient to use. The N-methyl group protects the sulfoximine reagent, the substrate applicability is also limited, when sodium thiophenolate and alcohol are used as substrates, the yield is very low, and the efficiency is lower for the difluoromethylation of an important C-nucleophilic agent.

CN107235878A discloses a series of electrophilic difluoromethylating agents of sulfur ylide type, their preparation method and application, but difluoromethyl etherification for alcohol requires 2.0 equivalents of substrate, otherwise the yield is less than 50%, and for important C-nucleophiles, only moderate yield of target product is obtained, and substrate adaptability is also limited.

Disclosure of Invention

Aiming at the key problem that the stability of the conventional electrophilic difluoromethylation reagent is poor, the invention synthesizes the electrophilic difluoromethylation reagent which is stably stored at room temperature by innovative design, and solves the problem of reagent stability. A series of electrophilic difluoromethylation reagents with different electronic effects and spatial structures are developed, difluoromethyl functionalization of different types of substrates can be met, a plurality of new difluoromethylation methods and new reactions are developed, and the reagents are solid, so that the use and operation are simple and convenient, and the operability is high.

The invention is based on diaryl difluoro methyl sulfonium salt type reagent, and realizes the self-stabilization of the reagent through the precise design and adjustment of the electronic effect and space effect in the reagent molecule, especially through the design of weak bonds such as hydrogen bond in the reagent molecule.

Specifically, the invention is realized by the following technical scheme:

a difluoromethylating agent characterized by comprising a compound having the following formula (I), (II) or (III) or a salt thereof,

wherein R is₁Is hydrogen, halogen, nitro, cyano, polyfluoroalkyl, C mono-or polysubstituted in the ortho-, meta-or para-position_1-20Alkyl of (C)_1-20Alkoxy or C_1-20One or more alkylthio groups; r₂Is C mono-or polysubstituted in ortho-, meta-or para-position_1-20Alkoxy group of (C)_1-20Alkylthio of, C_3-12Cycloalkoxy or C of_3-12One or more of the cycloalkylthio groups of (a); r₂O or S and CF in (1)₂H in H forms an intramolecular hydrogen bond.

The main principle of the invention realized by the reagent is as follows:

1. the key to the success of the difluoromethylation reagent of the present invention lies in the design of intramolecular hydrogen bonds and the adjustment of the electronic effect and the steric effect of the substituents on the aromatic ring. The hydrogen bond acceptor group (cyclo) alkoxy (sulfur) group is introduced to the benzene ring to form intramolecular hydrogen bond with hydrogen in difluoromethyl in the reagent, so that the method has important effects on the stability of the reagent and the regulation and control of the reaction activity. The hydrogen bond acceptor reduces the electropositivity of the positive charge part of the sulfonium salt through the electronic feedback of hydrogen bond to electrophilic difluoromethyl, thereby achieving the purpose of stabilizing the reagent, obtaining the reagent which is stable at room temperature, and being capable of adjusting the reaction activity of the reagent to ensure that the reagent has higher reaction activity and efficiency on various substrates, especially important C-nucleophilic agents.

2. Substituents with different steric and electronic effects (including electron donating and electron withdrawing) are introduced at different positions on the benzene ring. The two functions are that firstly, the stability of the reagent is further improved, secondly, the structure of the fluorinating agent is further optimized based on soft and hard acid-base theory, and the reaction activity of the reagent can be finely adjusted so as to meet the difluoromethyl functionalization of different types of substrates and develop a plurality of new difluoromethylation methods and new reactions.

As a preferred embodiment of the present invention,

the R is₁Wherein said hydrogen is protium, deuterium or tritium;

and/or, said R₁Wherein said halogen is fluorine, chlorine, bromine or iodine;

and/or, said R₁In (b), the C_1-20Alkyl of (A) is C_1-6Alkyl groups of (a);

and/or, said R₁In (b), the C_1-20Alkoxy of C_1-6Alkoxy group of (a);

and/or, said R₁In (b), the C_1-20Alkylthio of is C_1-6Alkylthio groups of (a);

and/or, said R₂In (b), the C_1-20Alkoxy of C_1-6Alkoxy group of (a);

and/or, said R₂In (b), the C_1-20Alkylthio of is C_1-6Alkylthio groups of (a);

and/or, said R₂In (b), the C_3-12With cycloalkoxy group of C_3-6Cycloalkoxy of (a);

and/or, said R₂In (b), the C_3-12With cycloalkylthio radical of C_3-6Cycloalkylthio group of (a);

and/or the hydrogen on the difluoromethyl group of the difluoromethylating agent is protium, deuterium or tritium.

As another preferred embodiment of the present invention, the salt of the difluoromethylating agent is a sulfonium salt, an anion of which is resistant to

Is tetrafluoroborate or hexafluorophosphate or triflate or fluorine, chlorine, bromine, iodine or phosphate, in particular of the following formulae (Ia), (IIa), (IIIa):

wherein the anti-anions in (Ia), (IIa), (IIIa)

Is tetrafluoroborate or hexafluorophosphate or trifluoromethanesulfonate;

further preferred, are anti-anions

Is tetrafluoroborate or hexafluorophosphate.

In another preferred embodiment, the sulfonium salt is a compound formed by difluoromethylating agent and anion of fluorine, chlorine, bromine, iodine or phosphate.

The stability and reactivity of the reagents is adjusted by the modification of the counter anion to the sulfonium salt. Different anionic nucleophilicity and alkalinity are different, and the weak bond forming ability and strength with difluoromethyl are different.

As another preferred embodiment of the present invention, the difluoromethylating agent is specifically selected from:

the invention further provides a preparation method of the difluoromethylation reagent, which comprises the following synthetic route:

wherein R is₁And R₂As described above. The reaction is carried out under the action of trifluoromethanesulfonic anhydride, and the selected solvent is one or more of diethyl ether, n-hexane, cyclohexane, dichloromethane, chloroform, toluene or tetrahydrofuran; the reaction temperature is from-80 ℃ to room temperature (preferably from-50 ℃ to room temperature, more preferably from-30 ℃ to room temperature, most preferably from-10 ℃ to room temperature); the aqueous solution of the salt is an aqueous solution of sodium tetrafluoroborate and/or potassium hexafluoroborate and/or potassium hexafluorophosphate and/or sodium chloride and/or potassium fluoride and/or potassium iodide and/or sodium phosphate, preferably sodium tetrafluoroborate and/or potassium hexafluoroborate.

The preparation method comprises the following steps: dissolving "difluoromethyl aryl sulfoxide or difluoromethyl heterocyclic sulfoxide" (e.g., difluoromethyl aryl sulfoxide in an amount of 0.8-1.2 equivalents, preferably 1.0 equivalent) and benzene with substituent R2 (e.g., alkoxybenzene in an amount of 1.0-1.5 equivalents, preferably 1.1 equivalents) in dry diethyl ether, and adding dropwise trifluoromethanesulfonic anhydride under stirring and nitrogen protection at-20 deg.C-25 deg.C (preferably-10 deg.C-15 deg.C, more preferably-5 deg.C, most preferably 0 deg.C); after the reaction (TLC monitoring), stopping stirring, standing, pouring out the ether phase at the upper layer, adding ether, continuously stirring, standing, pouring out the ether phase, and repeating the operation for more than 2 times (preferably 2-3 times); precipitating a solid, filtering, washing the filtered solid with diethyl ether, drying to obtain a sulfur onium trifluoromethanesulfonate, specifically S- (difluoromethyl) diaryltrifluoromethanesulfonate sulfur onium salt, dissolving the salt in an organic solvent, adding an aqueous solution of the salt (preferably 1M aqueous solution of sodium tetrafluoroborate or saturated aqueous solution of potassium hexafluoroborate) and stirring vigorously (preferably 10 minutes), standing, separating out the organic phase, repeating the process for more than 2 times (preferably 2-3 times), drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, crystallizing the product with dichloromethane and n-hexane (if the product is semisolid or liquid, separating and purifying by silica gel column chromatography), and obtaining the corresponding sulfur onium salt.

The reagent of the invention has wide difluoromethylation application value, and can develop different types of new difluoromethylation methods and new reactions.

Through a large number of experiments, the reagent is suitable for difluoromethylation of different types of substrates, such as difluoromethylation of nucleophiles like C, O, S, N, P or Se, and especially difluoromethylation of important C nucleophiles.

Specifically, the preparation method of the compound by difluoromethylation comprises the following routes, wherein 1 is the difluoromethylation reagent:

the alkali used in the reaction is NaH, KH, LiH, CaH₂、NaOH、KOH、LiOH、CsOH、Na₂CO₃、K₂CO₃、Cs₂CO₃、K₃PO₄、Na₃PO₄Etc., preferably NaH and/or LiOH.

The solvent used is tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, benzene, toluene, xylene, chlorobenzene, fluorobenzene, bromobenzene etc., preferably fluorobenzene and/or chlorobenzene and/or toluene. The reaction temperature is from-80 ℃ to 100 ℃, preferably from-30 ℃ to 50 ℃, more preferably from-10 ℃ to 35 ℃, more preferably from 0 ℃ to 25 ℃, and most preferably 0 ℃. The reaction time is 10 minutes to 12 hours, preferably 10 minutes to 6 hours, further preferably 10 minutes to 4.5 hours, more preferably 10 minutes to 3 hours, most preferably 20 minutes.

The following difluoromethylated compounds were obtained after difluoromethylation of the compounds:

the reaction method comprises the following steps:

the substrate 2 or 5 (e.g., preferably β -ketoester or malonate, 1.0 equivalent) is dissolved in a solvent (preferably fluorobenzene), the reaction temperature is-80 ℃ to 100 ℃ (preferably-30 ℃ to 50 ℃, more preferably-10 ℃ to 35 ℃, more preferably 0 ℃ to 25 ℃, most preferably 0 ℃), a base (preferably NaH and/or LiOH, 2.2 equivalents) is added, the mixture is stirred for 10 minutes to 12 hours (preferably 10 minutes to 6 hours, more preferably 10 minutes to 4.5 hours, more preferably 10 minutes to 3 hours, most preferably 20 minutes), the mixture is naturally raised to 18-30 ℃, the aforementioned difluoromethylating agent 1of the present invention is added, the mixture is stirred at room temperature for 10 minutes to 3 hours (preferably 10 minutes to 1.5 hours, more preferably 10 minutes to 45 minutes, more preferably 10 minutes to 30 minutes, most preferably 20 minutes), the mixture is quenched with a saturated aqueous ammonium chloride solution, ethyl acetate is extracted 2 times or more (preferably 3 times), the extraction phases are combined, the aqueous and the crude product is washed once with brine, dried, filtered, and the crude product is purified by silica gel chromatography under reduced pressure to obtain a purified 3-functional methyl difluoride product.

The stable novel electrophilic difluoromethyl reagent designed by the invention is used for developing a method and a strategy for introducing a difluoromethyl group at the α position of a carbonyl compound, including asymmetric difluoromethyl of the carbon at the α position of the carbonyl group, so that a solution is provided for efficiently and conveniently introducing the difluoromethyl group at the α position of the carbonyl group of organic compounds and drug molecules.

The difluoromethylated compound 3aa produced by the above reaction was used as a substrate and the following difluoromethyl-functionalized compound could be produced by further transformation:

the compounds 7 and 8 have the biological activities of resisting tumors and reducing blood sugar;

the compound 9 has anti-infective and analgesic biological activity.

Drawings

FIG. 1 is a drawing of certain difluoromethyl group-containing agents;

FIG. 2 is a schematic diagram of the principle of the difluoromethylation reagent of the present invention;

FIG. 3 is a single crystal diffraction pattern of the difluoromethylating agent 1a of the present invention;

FIG. 4 is a schematic representation of the reaction scheme for electrophilic C-selective difluoromethylation of carbonyl compounds with the difluoromethylating agents of the present invention (unless otherwise stated) 2(β -keto ester) or 5 (malonate) (1.0 eq.), base (2.2 eq.), 1(1.2 eq.), fluorobenzene, room temperature, 20 min. the yields and carbon/oxygen ratios of

products

3 and 6 are quantified by fluorine spectroscopy.

Fig. 5 is a schematic representation of the results of the electrophilic C-selective difluoromethylation of the reagents of the invention applied to carbonyl compounds, [ a ] LiOH as base, [ b ] NaH as base, Me ═ methyl, Et ═ ethyl, i-Pr ═ isopropyl, Bn ═ benzyl, Ph ═ phenyl.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.

General example a preparation of a difluoromethylating agent of the general formula:

wherein R is₁Is hydrogen, halogen, nitro, cyano, polyfluoroalkyl, C mono-or polysubstituted in the ortho-, meta-or para-position_1-20Alkyl of (C)_1-20Alkoxy or C_1-20One or more alkylthio groups; r₂Is C mono-or polysubstituted in ortho-, meta-or para-position_1-20Alkoxy group of (C)_1-20Alkylthio of, C_3-12Cycloalkoxy or C of_3-12One or more of the cycloalkylthio groups (C).

The preparation method comprises the following steps: an oven dried 50mL Schlenk flask was charged with "difluoromethyl aryl sulfoxide or difluoromethyl heterocyclic sulfoxide" RS (O) CF₂H (10mmol) and the substituent R₂Benzene (11mmol) and a magnetic stirrer; after argon is pumped and changed for three times, dried diethyl ether (20mL) is added under the protection of nitrogen, and the mixture is fully and evenly stirred; cooling the reaction liquid to 0 ℃, slowly dropwise adding trifluoromethanesulfonic anhydride (10mmol), standing for 2 minutes after dropwise adding, and removing the upper diethyl ether phase; 10mL of dry ether was added and stirred vigorously for 5 minutes, and the upper ether phase was removed; repeating the step for 3 times to separate out solids; filtering, and washing a filter cake for three times by using dry ether (10mL) to obtain a nearly white powdery trifluoromethanesulfonic acid sulfonium salt; this salt was dissolved in 30mL of dichloromethane and poured into a separatory funnel, 50mL of 1M sodium tetrafluoroborate solution was added and shaken vigorously for 5 minutes, separated and the aqueous phase was discarded. Repeating for 4 times, drying the organic phase by using an anhydrous sodium sulfate filter cake, evaporating the solvent at 30 ℃ under reduced pressure, and recrystallizing the product by using dichloromethane and n-hexane to obtain the corresponding sulfonium salt. Saturated potassium hexafluorophosphate solution is used to replace the sodium tetrafluoroborate solution to obtain hexafluorophosphate sulfonium salt.

The following examples the substituents of the parent nucleus were adjusted according to the methods described previously to give the following specific examples.

Example 1 following the procedure of the general formula, a compound of the formula:

the yield is 86%, the product is white crystalline powder, the melting point is 95.5-96.5 ℃.1H NMR (400MHz, CDCl3) δ 8.10(t, J ═ 54.6Hz, 1H), 7.72-7.64(m, 5H), 6.37(s, 2H), 3.99(s, 6H), 3.96(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.4, 163.0, 134.7, 131.5, 129.9, 120.9, 119.3(t, J ═ 298.0Hz), 93.1, 81.2, 57.5, 56.9; 19F NMR (376MHz, CDCl3) δ -97.7(dd, J ═ 233.6, 54.2Hz, 1F), -98.4(dd, J ═ 235.0, 56.2Hz, 1F), -153.8(s, 1F), -153.9(s, 3F); ms (esi): m/z 327(C16H1703F2S +). HRMS (ESI): calcd. for C16H1703F2S +: 327.0861, respectively; found: 327.0849.

example 2 following the procedure of the general formula, a compound of the formula:

the yield was 82%, the product was a white crystalline powder with a melting point of 104-. 1H NMR (400MHz, CDCl3) δ 7.87(dd, J ═ 56.2, 54.1Hz, 1H), 7.72-7.66(m, 5H), 6.35(s, 2H), 3.97(s, 6H), 3.95(s, 3H); 13CNMR (101MHz, CDCl3) δ 170.5, 163.0, 134.8, 131.6, 126.6, 120.7, 119.2(t, J296.5 Hz), 93.1, 80.6, 57.4, 56.8; 19F NMR (376MHz, CDCl3) δ -73.6(d, J ═ 711.1Hz, 6F), -97.0(dd, J ═ 233.5, 53.9Hz, 1F), -98.0(dd, J ═ 233.5, 53.9Hz, 1F); ms (esi): m/z 327(C16H1703F2S +); hrms (esi): calcd. for C16H1703F2S +: 327.0861, respectively; found: 327.0851.

example 3 following the procedure of the general formula above, a compound of the formula:

yield 66% and product as white crystalline powder with melting point 109.5-110.5 ℃.1H NMR (400MHz, CDCl3) δ 7.92(t, J ═ 54.9Hz, 1H), 7.74-7.62(m, 5H), 6.31(s, 2H), 4.28-4.16(m, 6H), 1.40(t, J ═ 7.0Hz, 3H), 1.31(t, J ═ 7.0Hz, 6H); 13C NMR (101MHz, CDCl3) δ 169.7, 162.3, 134.4, 131.4, 129.2, 121.0, 119.3(t, J ═ 298.0Hz), 93.8, 80.2, 66.6, 65.5, 14.4, 13.9; 19F NMR (376MHz, CDCl3) δ -96.1(d, J ═ 52.6Hz), -153.86, -153.91; ms (esi): m/z 369(C19H2303F2S +); hrms (esi): calcd. for C19H2303F2S +: 369.1331, respectively; found: 369.1323.

example 4 following the procedure of the general formula above, a compound of the formula:

yield 60% and product as white solid, melting point 76.3-77.3 ℃.1H NMR (400MHz, CDCl3) δ 7.84(dd, J ═ 55.6, 54.3Hz, 1H), 7.73-7.58(m, 5H), 6.24(s, 2H), 4.78-4.40(m, 3H), 1.35(d, J ═ 6.0Hz, 6H), 1.29(d, J ═ 6.1Hz, 6H), 1.23(d, J ═ 6.1Hz, 6H); 13C NMR (101MHz, CDCl3) δ 168.7, 161.6, 134.2, 131.4, 128.6, 121.4, 119.3(t, J ═ 298.9Hz), 94.7, 80.8, 74.1, 72.1, 21.81, 21.78, 21.35, 21.32; 19F NMR (376MHz, CDCl3) δ -95.5(dd, J ═ 225.6, 56.4Hz), -96.4(dd, J ═ 225.6, 56.40Hz), -153.9, -154.0; ms (esi): m/z 411(C22H2903F2S +); hrms (esi): calcd.for C22H2903F2S +: 411.1793, respectively; found: 411.1796.

example 5 following the procedure of the general formula above, a compound of the formula:

yield 40% product was a viscous oil. 1H NMR (400MHz, CDCl3) δ 7.59(t, J ═ 55.0Hz, 1H), 7.54-7.39(m, 5H), 6.10(s, 2H), 4.91-4.85(m, 3H), 1.82-1.35(m, 27H); 13C NMR (101MHz, CDCl3) δ 168.5, 161.5, 134.1, 128.3, 121.0, 119.1(t, J ═ 299.0Hz), 95.2, 83.1, 81.4, 79.6, 32.6, 32.4, 32.2, 23.9, 23.71, 23.67; 19F NMR (376MHz, CDCl3) δ -94.5(dd, J ═ 222.4, 54.2Hz), -95.3(dd, J ═ 222.4, 54.2Hz), -153.98, -154.03; ms (esi): m/z 489(C17H1903F2S +); hrms (esi): calcd.for C28H3503F2S +: 489.2270, respectively; found: 489.2262.

example 6 following the procedure of the general formula above, a compound of the formula:

yield 84% and product as white crystalline powder with melting point 119-. 1H NMR (400MHz, CDCl3) δ 7.81(t, J ═ 54.3Hz, 1H), 7.65(td, J ═ 9.2, 1.4Hz, 1H), 7.23(dd, J ═ 8.1, 1.2Hz, 1H), 7.18(d, J ═ 8.4Hz, 1H), 7.15(t, J ═ 8.0Hz, 1H), 6.37(s, 2H), 4.02(s, 3H), 3.96(s, 3H), 3.93(s, 6H); 13CNMR (101MHz, CDCl3) δ 170.2, 163.2, 158.4, 136.3, 129.7, 122.9, 119.5(t, J ═ 302.0Hz), 113.0, 108.1, 93.0, 79.6, 57.2, 57.1, 56.8; 19F NMR (376MHz, CDCl3) δ -95.4(dd, J ═ 214.3, 56.4Hz, 1F), -98.8(dd, J ═ 214.3, 56.4Hz, 1F), -153.56(s), -153.62(s); ms (esi): m/z 357(C17H1904F2S +); hrms (esi): calcd.for C17H1904F2S +: 357.0967, respectively; found: 357.0959.

example 7 following the procedure of the general formula above, a compound of the formula:

the yield is 82%, the product is white crystalline powder, the melting point is 94.8-95.8 ℃.1H NMR (400MHz, CDCl3) δ 8.11(t, J ═ 54.7Hz, 1H), 7.53(t, J ═ 8.2Hz, 1H), 7.24-7.16(m, 3H), 6.38(s, 2H), 3.98(s, 6H), 3.94(s, 3H), 3.83(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.4, 163.0, 161.3, 132.3, 121.9, 121.8, 121.0, 119.3(t, J ═ 296.9Hz), 114.4, 93.1, 81.4, 57.5, 56.9, 56.0; 19F NMR (376MHz, CDCl3) δ -96.8(dd, J ═ 233.1, 56.4Hz, 1F), -97.5(dd, J ═ 233.1, 56.4Hz, 1F), -152.78(s), -152.84(s); ms (esi): m/z 357(C17H1904F2S +); hrms (esi): calcd. forc17h1904f2s +: 357.0967, respectively; found: 357.0962.

example 8 following the procedure of the general formula, a compound of the formula:

the yield was 82%, the product was a white crystalline powder with a melting point of 125-. 1H NMR (400MHz, CDCl3) δ 8.11(t, J ═ 54.6Hz, 1H), 7.83(dd, J ═ 8.1, 0.7Hz, 1H), 7.74(d, J ═ 8.1Hz, 1H), 7.69(s, 1H), 7.60(t, J ═ 8.1Hz, 1H), 6.38(s, 2H), 3.99(s, 6H), 3.96(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.8, 163.1, 137.8, 133.1, 131.9, 128.6, 124.5, 122.7, 119.5(t, J ═ 299.0Hz), 93.2, 80.1, 57.6, 56.9; 19FNMR (376MHz, CDCl3) delta-97.8-99.4 (m), -153.4(s), -153.5(s); ms (esi): m/z 357(C17H1904F2S +); hrms (esi): calcd.for C17H1904F2S +: 357.0967, respectively; found: 357.0953.

example 9 following the procedure of the general formula, a compound of the formula:

yield 70% product as light brown solid, melting point 77.5-78.5 ℃.1H NMR (400MHz, CDCl3) δ 8.15(dd, J ═ 55.8, 54.2Hz, 1H), 7.41(dd, J ═ 8.6, 2.1Hz, 1H), 7.31(d, J ═ 2.1Hz, 1H), 7.09(d, J ═ 8.6Hz, 1H), 6.32(s, 2H), 4.01(s, 6H), 3.91(s, 3H), 3.90(s, 3H), 3.89(s, 3H); 13C NMR (101MHz, CDCl3) δ 189.8, 162.6, 155.1, 151.1, 126.5, 118.7(dd, J ═ 296.9, 293.9Hz), 112.8, 112.3, 110.5, 92.9, 84.2, 57.4, 56.7, 56.5, 56.5; 19F NMR (376MHz, CDCl3) δ -99.5(dd, J ═ 236.9, 56.4Hz, 1F), -100.6(dd, J ═ 236.9, 56.4Hz, 1F), -153.01(s), -153.07(s); ms (esi): m/z 387(C18H2105F2S +); hrms (esi): calcd. for C18H2105F2S +: 387.1072, respectively; found: 387.1066.

example 10 following the procedure of the general formula, a compound of the formula:

the yield was 73% and the product was a white crystalline powder with a melting point of 136.9-137.9 ℃.1H NMR (400MHz, CDCl3) δ 8.25(t, J ═ 54.6Hz, 1H), 7.88(d, J ═ 7.1Hz, 1H), 7.55(t, J ═ 6.3Hz, 1H), 7.47-7.40(m, 2H), 6.32(s, 2H), 3.99(s, 6H), 3.89(s, 3H), 2.58(s, 3H); 13C NMR (101MHz, CDCl3) δ 169.9, 162.6, 141.5, 134.9, 132.8, 131.4, 129.3, 120.7, 118.9(t, J ═ 295.9Hz), 93.0, 82.8, 57.4, 56.8, 19.9; 19FNMR (376MHz, CDCl3) delta-97.8-99.4 (m), -153.4(s), -153.5(s); ms (esi): m/z341(C17H1903F2S +); hrms (esi): calcd.for C17H1903F2S +: 341.1018, respectively; found: 341.1025.

example 11 following the procedure of the general formula, a compound of the formula:

the yield was 75% and the product was a white crystalline powder with a melting point of 86.9-87.9 ℃.1H NMR (400MHz, CDCl3) δ 8.06(dd, J ═ 55.9, 54.1Hz, 1H), 7.62(d, J ═ 8.3Hz, 2H), 7.46(d, J ═ 8.3Hz, 2H), 6.36(s, 2H), 4.01(s, 6H), 3.96(s, 3H), 2.43(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.2, 162.9, 146.5, 132.2, 130.2, 119.1(t, J ═ 341.4Hz), 117.2, 93.0, 82.0, 57.5, 56.8, 21.6; 19F NMR (376MHz, CDCl3) δ -97.9(dd, J ═ 236.9, 56.4Hz, 1F), -98.8(dd, J ═ 236.9, 56.4Hz, 1F), -153.45(s), -153.51(s); ms (esi): m/z341(C17H1903F2S +); hrms (esi): calcd. forc17h1903f2s +: 341.1018, respectively; found: 341.1012.

example 12 following the procedure of the general formula, a compound of the formula:

the yield is 82%, the product is white crystalline powder, the melting point is 144.5-145.5 ℃.1H NMR (400MHz, CDCl3) δ 8.31(t, J ═ 55.0Hz, 1H), 7.70(s, 1H), 7.38(d, J ═ 7.9Hz, 1H), 7.30(d, J ═ 7.9Hz, 1H), 6.34(s, 2H), 4.03(s, 6H), 3.94(s, 3H), 2.55(s, 3H), 2.39(s, 3H); 13C NMR (101MHz, CDCl3) δ 169.8, 162.6, 139.9, 138.4, 136.0, 132.5, 131.4, 120.3, 118.9(t, J ═ 295.9Hz), 93.0, 83.3, 57.4, 56.8, 20.9, 19.4.

19F NMR(376MHz，CDCl3)δ-98.6(dd，J＝236.9，56.4Hz，1F)，-99.4(dd，J＝236.9，56.4Hz，1F)，-153.28(s)，-153.33(s)；MS(ESI)：m/z 355(C18H2103F2S+)；HRMS(ESI)：calcd.for C18H2103F2S+：355.1174；Found：355.1169.

Example 13 following the procedure of the general formula, a compound of the formula:

the preparation temperature is-20 ℃, the yield is 22%, the product is white crystalline powder, and the melting point is 96.7-97.7 ℃.1H NMR (400MHz, CDCl3) δ 8.16(t, J ═ 54.4Hz, 1H), 7.78-7.73(m, 1H), 7.71-7.67(m, 1H), 7.50(t, J ═ 7.9Hz, 1H), 7.38(t, J ═ 9.0Hz, 1H), 6.37(s, 2H), 4.00(s, 6H), 3.96(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.7, 163.2, 160.9(d, J ═ 257.6Hz), 137.4(d, J ═ 8.1Hz), 131.4, 127.4, 119.5(t, J ═ 300.0Hz), 117.7(d, J ═ 20.2Hz), 108.4(d, J ═ 16.2Hz), 93.2, 79.3, 57.5, 56.8; 19F NMR (376MHz, CDCl3) δ -96.2(d, J ═ 56.4Hz, 2F), -107.7(s, 1F), -153.1(s); ms (esi): m/z 345(C16H1603F3S +); hrms (esi): calcd.for C16H1603F3S +: 345.0767, respectively; found: 345.0767.

example 14 following the procedure of the general formula, a compound of the formula:

the preparation temperature was-20 ℃ with a yield of 38% and the product was a colorless viscous oil. 1H NMR (400MHz, CDCl3) δ 8.07(t, J ═ 54.6Hz, 1H), 7.71-7.65(m, 1H), 7.52(d, J ═ 8.0Hz, 1H), 7.39(td, J ═ 8.2, 2.1Hz, 1H), 7.34(dt, J ═ 7.7, 1.8Hz, 1H), 6.36(s, 2H), 3.95(s, 6H), 3.92(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.8, 163.1, 163.0(d, J ═ 256.2Hz), 133.4(d, J ═ 8.1Hz), 125.9(d, J ═ 3.3Hz), 122.4, 122.2(d, J ═ 52.2Hz), 119.5(t, J ═ 271.1Hz), 116.6, 93.2, 80.1, 57.5, 56.8; 19F NMR (376MHz, CDCl3) δ -96.8(d, J ═ 54.4Hz, 2F), -106.2(m, 1F), -152.5(s), -152.6(s); ms (esi): m/z 345(C16H1603F3S +); hrms (esi): calcd.for C16H1603F3S +: 345.0767, respectively; found: 345.0767.

example 15 following the procedure of the general formula, a compound of the formula:

the preparation temperature is-20 ℃, the yield is 19 percent, and the product is white crystalline powder with the melting point of 113.5-114.5 ℃. 1HNMR (400MHz, CDCl3) δ 8.12(dd, J ═ 55.8, 54.2Hz, 1H), 7.66-7.64(m, 3H), 7.55(s, 1H), 6.38(s, 2H), 3.98(s, 6H), 3.96(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.8, 163.1, 137.0, 134.8, 132.9, 129.1, 128.2, 122.6, 119.5(t, J ═ 299.0Hz), 93.2, 80.1, 57.5, 56.9; 19F NMR (376MHz, CDCl3) δ -96.6(d, J ═ 52.6Hz, 2F), -153.13(s), -153.19(s); ms (esi): m/z 361(C16H1603ClF2S +); hrms (esi): calcd. for C16H1603ClF2S +: 361.0471, respectively; found: 361.0468.

example 16 following the procedure of the general formula above, a compound of the formula:

the preparation temperature is-20 ℃, the yield is 41 percent, and the product is white crystalline powder with the melting point of 114.9-115.9 ℃. 1HNMR (400MHz, CDCl3) δ 8.11(t, J ═ 54.6Hz, 1H), 7.83(dd, J ═ 8.1, 0.7Hz, 1H), 7.74(d, J ═ 8.1Hz, 1H), 7.69(s, 1H), 7.60(t, J ═ 8.1Hz, 1H), 6.38(s, 2H), 3.99(s, 6H), 3.96(s, 3H); 13CNMR (101MHz, CDCl3) δ 170.8, 163.1, 137.8, 133.1, 131.9, 128.6, 124.5, 122.7, 119.5(t, J ═ 299.0Hz), 93.2, 80.1, 57.6, 56.9; 19F NMR (376MHz, CDCl3) δ -96.5(d, J ═ 56.4Hz), -153.05(s), -153.10(s); ms (esi): m/z 405(C16H1603BrF2S +); hrms (esi): calcd. forc16h1603brf2s +: 404.9966, respectively; found: 404.9963.

example 17 following the procedure of the general formula above, a compound of the formula:

the preparation temperature is-20 ℃, the yield is 55%, the product is white crystalline powder, and the melting point is 115.9-116.9 ℃. 1HNMR (400MHz, CDCl3) δ 8.12(t, J ═ 54.9Hz, 1H), 7.77(d, J ═ 8.8Hz, 2H), 7.63(d, J ═ 8.8Hz, 2H), 6.35(s, 2H), 3.98(s, 6H), 3.94(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.6, 163.0, 134.7, 131.5, 130.2, 120.0, 119.1(t, J ═ 298.0Hz), 93.1, 80.9, 57.5, 56.8; 19F NMR (376MHz, CDCl3) δ -97.6(dd, J ═ 233.1, 56.4Hz, 1F), -98.3(dd, J ═ 233.1, 56.4Hz, 1F), -152.9(s), -153.0(s); ms (esi): m/z 405(C16H1603BrF2S +); hrms (esi): calcd. for C16H1603BrF2S +: 404.9966, respectively; found: 404.9952.

example 18 following the procedure of the general formula, a compound of the formula:

the yield was 73% and the product was a white crystalline powder with a melting point of 115.9-116.9 ℃.1H NMR (400MHz, CDCl3) δ 8.34(d, J ═ 1.1Hz, 1H), 8.23(t, J ═ 55.4Hz, 1H), 8.07(d, J ═ 8.9Hz, 1H), 8.02(d, J ═ 8.0Hz, 1H), 7.86(d, J ═ 8.1Hz, 1H), 7.67-7.57(m, 3H), 6.35(s, 2H), 3.99(s, 6H), 3.93(s, 3H); 13CNMR (101MHz, CDCl3) δ 170.3, 163.0, 135.3, 133.1, 132.7, 132.0, 130.3, 129.2, 128.6, 128.1, 123.5, 119.0(t, J ═ 298.0Hz), 117.6, 93.1, 82.1, 57.5, 56.8; 19F NMR (376MHz, CDCl3) δ -97.9(dd, J ═ 233.1, 52.6Hz, 1F), -98.7(dd, J ═ 233.1, 52.6Hz, 1F), -152.89(s), -152.94(s); ms (esi): m/z 377(C20H1903F2S +); hrms (esi): calcd. for C20H1903F2S +: 377.1018, respectively; found: 377.1014.

example 19 following the procedure of the general formula above, a compound of the formula:

the yield was 75% and the product was a white crystalline powder with a melting point of 104-. 1H NMR (400MHz, CDCl3) δ 8.28(s, 1H), 8.08(d, J ═ 8.9Hz, 1H), 8.01(t, J ═ 55.9Hz, 1H), 8.01(d, J ═ 7.7Hz, 1H), 7.88(d, J ═ 7.5Hz, 1H), 7.67-7.60(m, 3H), 6.34(s, 2H), 3.98(s, 6H), 3.94(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.4, 163.0, 135.3, 133.1, 132.5, 132.1, 130.4, 129.2, 128.7, 128.1, 123.1, 117.4(t, J ═ 296.9Hz), 116.0, 93.1, 81.6, 57.4, 56.7; 19F NMR (376MHz, CDCl3) δ -73.3(d, J ═ 714.4Hz, 6F), -97.7(dd, J ═ 233.1, 56.4Hz, 1F), -98.3(dd, J ═ 233.1, 56.4Hz, 1F); ms (esi): m/z 377(C17H1903F2S +); hrms (esi): calcd. for C20H1903F2S +: 377.1018, respectively; found: 377.1013.

example 20 following the procedure of the general formula preparation gave the compound of the formula:

the yield was 70% and the product was a white crystalline powder with melting point 117-. 1H NMR (400MHz, CDCl3) δ 8.08(d, J ═ 4.8Hz, 1H), 8.03(d, J ═ 3.7Hz, 1H), 7.95(dd, J ═ 55.9, 54.5Hz, 1H), 7.28(dd, J ═ 4.8, 3.7Hz, 1H), 6.34(s, 2H), 4.07(s, 6H), 3.93(s, 3H); 13C NMR (101MHz, CDCl3) δ 170.4, 162.6, 142.8, 140.9, 129.0, 118.8(t, J ═ 230.0Hz), 114.7, 92.8, 84.5, 57.4, 56.9; 19F NMR (376MHz, CDCl3) δ -97.5(dd, J ═ 243.4, 57.7Hz, 1F), -100.9(dd, J ═ 243.4, 57.7Hz, 1F), -152.9(s), -153.0(s); ms (esi): m/z 333(C14H1503F2S2 +); hrms (esi): calcd. forc14h1503f2s2 +: 333.0425, respectively; found: 333.0419.

example 21 following the procedure of the general formula above, a compound of the formula:

yield 84% and product as white crystalline powder, melting point 116.1-117.1 ℃.1H NMR (500MHz, CDCl3) delta 7.74-7.70(m, 3H), 7.68-7.65(m, 2H), 6.37(s, 2H), 4.00(s, 6H), 3.97(s, 3H); 13C NMR (126MHz, CDCl3) δ 170.4, 163.0, 134.7, 131.5, 129.9, 120.9, 119.0(tt, J ═ 294.8, 39.1Hz), 93.0, 81.2, 57.5, 56.9; 19F NMR (376MHz, CDCl3) δ -97.6(dt, J ═ 223.1, 7.5Hz), -98.3(dt, J ═ 223.1, 7.5Hz), -153.5, -153.6.ms (esi): m/z 328(C16H162H03F2S +; hrms (esi): calcd.for C16H162H03F2S +: 328.0924, respectively; found: 328.0913.

example 22 following the procedure of the general formula, a compound of the formula:

the yield was 81%, the product was a white crystalline powder with a melting point of 97-98 ℃.1H NMR (400MHz, CDCl3) delta 7.73-7.62(m, 5H), 7.34(s, 2H), 3.96(s, 6H), 3.94(s, 3H); 13C NMR (126MHz, CDCl3) delta 170.5, 163.0, 134.8, 131.6, 129.6, 120.7, 93.1, 80.7, 57.4, 56.7; 19F NMR (376MHz, CDCl3) δ -73.6(d, J-711.1 Hz), -97.9(d, J-233.9 Hz), -98.8(d, J-233.9 Hz). m/z 328(C16H162H03F2S +; hrms (esi): calcd.for C16H162H03F2S +: 328.0924, respectively; found: 328.0917.

general example B, use of difluoromethylating agent:

a method for the selective C-difluoromethylation of carbonyl compounds (3-ketoesters, malonates, etc.), 3-ketoesters 2 and malonates 5 represented by the following general formulae:

the method comprises the following steps: a25 mL oven dried Schlenk tube was taken, substrate (0.2 mmol, 3-keto ester or malonate, 1.0 equiv.) was added and dissolved in 2.0mL fluorobenzene, LiOH (0.44 mmol, 2.2 equiv.) was added at 0 deg.C when cooled, stirred at this temperature for 20 minutes, warmed to room temperature naturally, difluoromethylating agent 1 was added and stirred at room temperature for 20 minutes, quenched with saturated aqueous ammonium chloride, extracted 3 times with ethyl acetate, the extract phases were combined, water and brine were washed once each, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography to give pure difluoromethyl functionalized product.

Example 23 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

methyl-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3aa).

The C/O ratio was 97: 3 by fluorimetry, the isolation yield was 87%, and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 8.04(dd, J ═ 8.0, 1.4Hz, 1H), 7.53(td, J ═ 8.0, 1.4Hz, 1H), 7.33(t, J ═ 7.6Hz, 1H), 7.26(d, J ═ 7.6Hz, 1H), 6.60(t, J ═ 55.2Hz, 1H), 3.75(s, 3H), 3.32(ddd, J ═ 17.0, 11.5, 5.0Hz, 1H), 3.04(dt, J ═ 17.0, 4.5Hz, 1H), 2.66 (127, J ═ 14.0, 4.5Hz, 1H), 2.46(ddd, J ═ 14.0, 11.5, 376.0, 1H), 376H (19, J ═ 14.0, 19H, 19H, 3.52H, 35H, 11H, 11.52H, 11H, 35H, 11H, 3H: m/z 277.1(C13H12F203Na +).

Example 24 following the procedure of the general formula above, using difluoromethyl reagent 1b, the compound of the formula:

methyl-2- (difluoromethyl) -5-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-5-methoxy-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ab).

The C/O ratio was 97: 3 as determined by fluorimetry, the isolation yield was 78%, and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 7.58(dd, J-8.0, 1.1Hz, 1H), 7.22(t, J-8.0 Hz, 1H), 6.98(dd, J-8.0, 1.1Hz, 1H), 6.50(t, J-55.3 Hz, 1H), 3.80(s, 3H), 3.65(s, 3H), 3.07(ddd, J-18.0, 5.7, 3.6Hz, 1H), 2.93(ddd, J-18.0, 11.2, 5.5Hz, 1H), 2.61(ddd, J-14.0, 5.5, 3.6Hz, 1H), 2.30(ddd, J-14.0, 11.2, 5.376, 1H, 19H, 19.0, 7.7H), 7H, 18.7H, 7H, 18.7H, 7H, 26H, 7H, 18H, 7H, 18H, 7H, 18H, 7H, 18H, 7H, 18, j ═ 21.4Hz), 55.7, 53.2, 22.5(t, J ═ 3.8Hz), 18.8.ms (esi): m/z 307.1(C14H14F204Na +), HRMS (ESI): calcd. for C14H15F204 +: 285.0933, respectively; found: 285.0923.

example 25 following the procedure of the general formula above, using difluoromethyl reagent 1c, the compound of the formula:

methyl-2- (difluoromethyl) -6-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-6-methoxy-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ac).

The C/O ratio was 96: 4 by fluorimetry, the isolated yield was 80% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 8.00(d, J ═ 8.8Hz, 1H), 6.83(dd, J ═ 8.8, 2.5Hz, 1H), 6.68(d, J ═ 2.5Hz, 1H), 6.61(t, J ═ 55.4Hz, 1H), 3.86(s, 3H), 3.74(s, 3H), 3.31(ddd, J ═ 17.0, 11.5, 5.0Hz, 1H), 2.98(dt, J ═ 17.0, 4.5Hz, 1H), 2.62(dt, J ═ 13.9, 4.5Hz, 1H), 2.43(ddd, J ═ 13.9, 11.5, 5.1Hz, 1H), 19F (376, cl 8584, cl ═ 0, 7.282 ═ 7.282, 15H), 15.7.7H, 7H, — (ddd, 7.282), 15.9, 7.5.5 Hz, 1H, — (dd: m/z 307.1(C14H14F204Na +).

Example 26 following the procedure of the general formula above, using 1d as difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -7-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-7-methoxy-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ad).

The C/O ratio was 92: 8 by fluorimetry, the isolated yield was 77% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.42(d, J ═ 2.8Hz, 1H), 7.09(d, J ═ 8.5Hz, 1H), 7.03(dd, J ═ 8.5, 2.8Hz, 1H), 6.51(t, J ═ 55.3Hz, 1H), 3.75(s, 3H), 3.67(s, 3H), 3.15(ddd, J ═ 16.8, 11.5, 5.0Hz, 1H), 2.89(dt, J ═ 17.0, 4.5Hz, 1H), 2.56(dt, J ═ 13.9, 4.5Hz, 1H), 2.35(ddd, J ═ 13.8, 11.5, 5.2Hz, 1H), 19 (376, cl3, 283, 19.8, 4.5Hz, 1H), 2.35(ddd, 13.8, 11.5, 5.2Hz, 1H, 19 MHz, 283, 7.8, 35(ddd, 3.8, 23.8H, 23H, 23.8, 23H, 23H, 23H, 23, 2, 55.5, 53.2, 24.2, 23.4(t, J ═ 3.8Hz). m/z 307.1(C14H13F204Na +), HRMS (ESI): calcd. for C14H15F204 +: 285.0933, respectively; found: 285.0923.

example 27 following the procedure of the general formula above, using 1e as the difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -6, 7-dimethoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-6，7-dimethoxy-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ae).

The C/O ratio was 93: 7 as determined by fluorimetry, the isolation yield was 85%, the product was a white solid, melting point 86-88 ℃.1H NMR (400MHz, CDCl3) δ 7.46(s, 1H), 6.64(s, 1H), 6.60(t, J ═ 55.4Hz, 1H), 3.92(s, 3H), 3.88(s, 3H), 3.73(s, 3H), 3.26(ddd, J ═ 17.0, 11.0, 5.0Hz, 1H), 2.92(dt, J ═ 17.0, 4.5Hz, 1H), 2.61(dt, J ═ 14.0, 4.5Hz, 1H), 2.42(ddd, J ═ 14.0, 11.0, 5.0Hz, 1H), 19F NMR (376MHz, CDCl3) δ -128.1 (J ═ 283.2, 55.3, 1H 132.7 (ddl, 1H), 1H ═ 19F NMR (376MHz, CDCl3) δ -128.1 (J ═ 2.7, J ═ 19H, 19H), 19H (esi, 19H, 7, 19J ═ 20, 19H, 19J ═ esi, 19H, 7, 19, 7, 19H, 19J ═ H, 19H, 19J ═ d, 19H, 19: m/z 337.1(C15H16F205Na +), HRMS (ESI): calcd.for C15H17F205 +: 315.1039, respectively; found: 315.1027.

example 28 following the procedure of the general formula, using 1f as the difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -5, 7-dimethyl-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-5，7-dimethyl-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3af).

The C/O ratio was 91: 9 as determined by fluorimetry, the isolation yield was 70%, the product was a white solid, melting point 87-89 ℃.1H NMR (400MHz, CDCl3) δ 7.73(d, J ═ 2.0Hz, 1H), 7.23(d, J ═ 2.0Hz, 1H), 6.59(t, J ═ 55.3Hz, 1H), 3.73(s, 3H), 3.07(ddd, J ═ 17.0, 11.0, 5.0Hz, 1H), 2.94(ddd, J ═ 17.0, 5.4, 3.5Hz, 1H), 2.69(ddd, J ═ 14.0, 5.0, 3.5Hz, 1H), 2.39(ddd, J ═ 14.0, 11.0, 5.6Hz, 1H), 2.33(s, 3H), 2.27(s, 3H), 19 MHz, 36376- δ 7.0, 11.0, 5.6Hz, 1H), 2.33(s, 3H), 2.27(s, 3H), 19 (cl), 376- Δ 7.7.7, 7.7.3.7, 7.8, 7.3Hz, 7.3H, 7.2.3H, 7.3H, 18H, 7.2.3H, 7.2.2.2.3H, 7.3H, 7.2.2.3H, 7.2.2.2.2.2.2.2.3H, 18H, 7H, 7.3H, j ═ 3.5Hz), 22.0, 20.8, 19.1.ms (esi): m/z 305.1(C15H16F203Na +), HRMS (ESl): calcd.for C15H17F203 +: 283.1140, respectively; found: 283.1131.

example 29 following the procedure of the general formula, using 1g of difluoromethyl reagent, the compound of the formula:

methyl-6-bromo-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-6-bromo-2-(difluoromethyl)-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ag).

The C/O ratio was 96: 4 by fluorimetry, the isolation yield was 83%, the product was a white solid with a melting point of 45-47 ℃.1H NMR (400MHz, CDCl3) δ 7.90-7.45(m, 3), 6.58(t, J ═ 55.2Hz, 1H), 3.75(s, 3H), 3.30(ddd, J ═ 17.0, 11.5, 5.0Hz, 1H), 3.00(dt, J ═ 17.0, 4.0Hz, 1H), 2.65(ddd, J ═ 14.0, 5.0, 4.0Hz, 1H), 2.44(ddd, J ═ 14.0, 11.5, 5.0Hz, 1H), 19F NMR (376MHz, CDCl3 dd) δ -127.3 (J ═ 284.2, 55.4Hz, 1H), -131.7(dd, J ═ 284.3, 56.0, 1H) δ -13C (101.90-7.45, m, 3), 6.23.7 (t, 18.8Hz, 18.7, 18.8H), 18.7 (35 Hz, 18.7, 18.8H, 18.7, 18, 18.8H, 18, 18.7 (18, 7, 18, 8, 18: m/z 354.9(C13H11BrF203Na +), HRMS (ESI): calcd. for C13H12BrF203 +: 332.9932, respectively; found: 332.9923.

example 30 following the procedure of the general formula above, difluoromethyl reagent for 1h, the compound of the formula:

methyl-2- (difluoromethyl) -6-fluoro-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-6-fluoro-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ah).

The C/O ratio was 92: 8 by fluorimetry, the isolated yield was 86% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 8.07(dd, J-9.0, 5.9Hz, 1H), 7.02(td, J-8.5, 2.5Hz, 1H), 6.94(dd, J-9.0, 2.5Hz, 1H), 6.60(t, J-55.2 Hz, 1H), 3.76(s, 3H), 3.33(ddd, J-17.0, 11.5, 5.1Hz, 1H), 3.02(dt, J-17.0, 4.5Hz, 1H), 2.65(dt, J-14.0, 4.5Hz, 1H), 2.46(ddd, J-14.0, 11.5, 5.1Hz, 1H), 19F (376MHz, cl-8, 57.57, 18.7H, 18H, 18.55H, 18H, 35H, 18H, 35H, 18, 127.7(d, J ═ 2.4Hz), 115.7(t, J ═ 246.7Hz), 115.3(d, J ═ 21.6Hz), 115.0(d, J ═ 22.3Hz), 60.7(t, J ═ 21.8Hz), 53.3, 25.2, 23.0(t, J ═ 3.9Hz) ms (esi): m/z 295.1(C13H11F303Na +), HRMS (ESI): calcd. for C13H12F303 +: 273.0733, respectively; found: 273.0723.

example 31 following the procedure of the general formula above, using 1i as difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -7-fluoro-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-2-(difluoromethyl)-7-fluoro-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ai).

The C/O ratio was 93: 7 by fluorimetry, the isolated yield was 85% and the product was a pale yellow liquid. 1H NMR (500MHz, CDCl3) δ 8.29-7.17(m, 3H), 6.60(t, J-55.2 Hz, 1H), 3.78(s, 3H), 3.28(ddd, J-17.0, 11.5, 5.0Hz, 1H), 3.04(dt, J-17.0, 4.5Hz, 1H), 2.69(dt, J-14.0, 4.5Hz, 1H), 2.47(ddd, J-14.0, 11.5, 5.0Hz, 1H), 19F NMR (376MHz, CDCl3) δ -102.8(s, 1H), -127.9(dd, J-283.0, 54.8Hz, 1H), -132.3(dd, J-284.2, 54.9, 1H), 1H, -132.3 (ddd, J-2, 54.9, 13H, 13.9 (m, 3H), 7.7.7H), 18, 18.7.7H, 18, 18.7H, 18H, 18.3 (ddd, 18.7H), 2H, 18H, 114.0(d, J ═ 22.3Hz), 60.6(t, J ═ 21.7Hz), 53.4, 24.4, 23.3(t, J ═ 3.8Hz). m/z 295.1(C13H11F303Na +), HRMS (ESI): calcd. for C13H12F303 +: 273.0733, respectively; found: 273.0725.

example 32 following the procedure of the general formula, using 1j for difluoromethylating the reagent, the compound of the formula:

methyl-7-chloro-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Methyl-7-chloro-2-(difluoromethyl)-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3aj).

The c/O ratio was 93: 7 as determined by fluorimetry, the isolation yield was 78%, the product was a pale yellow solid, m.p. 63-65 ℃.1H NMR (400MHz, CDCl3) δ 7.99(d, J ═ 2.3Hz, 1H), 7.48(dd, J ═ 8.3, 2.3Hz, 1H), 7.22(d, J ═ 8.2Hz, 1H), 6.57(t, J ═ 55.2Hz, 1H), 3.75(s, 3H), 3.26(ddd, J ═ 16.9, 11.5, 5.0Hz, 1H), 3.01(dt, J ═ 17.4, 4.6Hz, 1H), 2.66(dt, J ═ 14.0, 4.5Hz, dd1H), 2.44(d, J ═ 14.1, 11.5, 5.1Hz, 1H), 19F NMR (376, CDCl3) δ -127.7(dd, J ═ 14.7, J ═ 14.60, 18, 18.7, 26, 18H, 18, 18.7, 18H, 18H, 18.7, 18H, 18H, 18.7, 18H, 35, 18H, 18: m/z 311.0(C13H11ClF203Na +), HRMS (ESI): calcd. forc13h12clf203 +: 289.0438, respectively; found: 289.0431.

example 33 following the procedure of the general formula, using 1k difluoromethyl reagent, the compound of the formula:

ethyl-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Ethyl-2-(difluoromethyl)-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3ak).

The C/O ratio was 96: 4 by fluorimetry, the isolation yield was 84%, and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 8.05(dd, J ═ 7.6, 1.5Hz, 1H), 7.54(td, J ═ 7.5, 1.5Hz, 1H), 7.34(t, J ═ 7.6Hz, 1H), 7.28(d, J ═ 7.5Hz, 1H), 6.62(t, J ═ 55.3Hz, 1H), 4.32-4.15(m, 2H), 3.35(ddd, J ═ 16.9, 11.5, 5.0Hz, 1H), 3.05(dt, J ═ 17.3, 4.6Hz, 1H), 2.127.68 (dt, J ═ 13.9, 4.7Hz, 1H), 2.47(ddd, J ═ 14.0, 11.5, 5.2, 1H, 2.2H, 2.2.2H, 3H, 3.2.9, 3.7H, 3H, 3.2.47 (ddd, 14.0, 3, 3.3, 3H, 2.2, 3H, 35H, 3H, 35H, 3H, 35H, 2H, 35H, 3H, 13H, 3H, 128.9, 128.2, 127.0, 115.9(t, J ═ 246.6Hz), 62.5, 60.8(t, J ═ 21.4Hz), 25.0, 23.1(t, J ═ 3.8Hz), 13.9.ms (esi): m/z 291.0(C14H14F203Na +), HRMS (ESI): calcd. for C14H15F203 +: 269.0984, respectively; found: 269.0974.

example 34 following the procedure of the general formula above, using 1I as the difluoromethylating agent, the compound of the formula:

allyl-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate

Allyl-2-(difluoromethyl)-1-oxo-1，2，3，4-tetrahydronaphthalene-2-carboxylate(3al).

The C/O ratio was 97: 3 by fluorimetry, the isolated yield was 82% and the product was a light red oily liquid. 1H NMR (400MHz, CDCl3) δ 8.06(dd, J-7.9, 1.4Hz, 1H), 7.55(td, J-7.5, 1.5Hz, 1H), 7.35(t, J-7.6 Hz, 1H), 7.28(d, J-7.7 Hz, 1H), 6.64(t, J-55.2 Hz, 1H), 5.84(ddt, J-17.2, 10.8, 5.5Hz, 1H), 5.31-5.14(m, 2H), 4.70-4.63(m, 2H), 3.35(ddd, J-16.8, 11.5, 4.9Hz, 1H), 3.06(dt, J-17.3, 4.6, 1H), 376, 70, J-16.8, 11.5, 4.9Hz, 1H), 3.06 (dd, J-17.3, 4.6, 3, 18, 19H), 23, 19H, 18H, 19H, 18H, 8H, 18H, 143.5, 134.5, 131.1(d, J ═ 2.3Hz), 130.8, 128.9, 128.2, 127.0, 118.9, 115.8(t, J ═ 246.7Hz), 66.6, 60.9(t, J ═ 21.4Hz), 25.0, 23.1(t, J ═ 3.8Hz), ms (esi): m/z 303.1(C15H14F203Na +), HRMS (ESI): calcd. for C15H15F203 +: 281.0984, respectively; found: 281.0973.

example 35 following the procedure of the general formula above, using 1m of difluoromethyl reagent, the compound of the formula:

methyl-3- (difluoromethyl) -4-oxochroman-3-carboxylic acid ester

Methyl-3-(difluoromethyl)-4-ox℃hroman-3-carboxylate(3am).

The C/O ratio was 97: 3 by fluorimetry, the isolated yield was 86% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.95(dd, J ═ 7.9, 1.8Hz, 1H), 7.56(ddd, J ═ 8.7, 7.2, 1.8Hz, 1H), 7.09(td, J ═ 7.7, 7.3, 1.0Hz, 1H), 7.04(dd, J ═ 8.4, 1.0Hz, 1H), 6.59(t, J ═ 54.3Hz, 1H), 5.06(d, J ═ 12.0Hz, 1H), 4.75(d, J ═ 12.0Hz, 1H), 3.83(s, 3H), 19F NMR (376MHz, CDCl3) δ -127.2(dd, J ═ 287.5, 54.5, 1.5, 1H, 130.4 (ddl, 130.7H), 3H), 19F NMR (376MHz, CDCl3) δ -127.2(dd, J ═ 287.5, 54.5, 7.53, 7.60, 7.3H, 18H, 13H, 7.3H, 3H, 18H, 3H, 7.3H: m/z 279.0(C12H1OF204Na +), HRMS (ESI): calcd. for C12H11F204 +: 257.0620, respectively; found: 257.0620.

example 36 following the procedure of the general formula, using 1n as the difluoromethylating agent, the compound of the formula:

methyl-3- (difluoromethyl) -4-oxothiochrome-3-carboxylic acid esters

Methyl-3-(difluoromethyl)-4-oxothi℃hroman-3-carboxylate(3an).

The C/O ratio was 97: 3 by fluorimetry, the isolated yield was 53%, the product was a pale yellow solid with a melting point of 89-91 ℃.1H NMR (400MHz, CDCl3) δ 8.15(dd, J-8.1, 1.6Hz, 1H), 7.41(ddd, J-8.4, 7.2, 1.5Hz, 1H), 7.22(ddd, J-15.1, 7.9, 1.5Hz, 2H), 6.52(dd, J-55.5, 54.1Hz, 1H), 3.78(s, 1H), 3.68(d, J-13.7 Hz, 1H), 3.54(d, J-13.7 Hz, 1H), 19F (376MHz, CDCl3) δ -126.4(dd, J-283.5, 54.1Hz, 1H), -130.5 (esi, J-6, 55.283H, 1H), 101.7H, 101.7 MHz, 130.7H, 7.7Hz, 7H), 367.7H, (35 Hz, 7H), 19H, (35H, 7H), 7H, 18H, 7H, 54.7H, 7H: m/z 295.0(C12H10F203SNa +), HRMS (ESI): calcd. for C12H11F203S +: 273.0392, respectively; found: 273.0381.

example 37 following the procedure of the general formula above, using 1o difluoromethyl reagent, the compound of the formula:

methyl-6- (difluoromethyl) -5-oxo-6, 7, 8, 9-tetrahydro-5H-benzo [7] annulene-6-carboxylate

Methyl-6-(difluoromethyl)-5-oxo-6，7，8，9-tetrahydro-5H-benzo[7]annulene-6-carboxylate(3c).

The C/O ratio was 96: 4 by fluorimetry, the isolation yield was 84%, and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 7.38(dd, J ═ 7.5, 1.5Hz, 1H), 7.33(td, J ═ 7.5, 1.5Hz, 1H), 7.21(d, J ═ 7.5Hz, 1H), 7.08(d, J ═ 7.5Hz, 1H), 6.33(t, J ═ 55.2Hz, 1H), 3.58(s, 3H), 3.22-1.76(m, 6H).19F NMR (MHz, CDCl3) δ -127.2(d, J ═ 46.5Hz, 1H), -127.3(d, J ═ 47.3Hz, 1H) — (ms), (esi): m/z291.1(C14H14F203Na +).

Method two, taking a 25mL Schlenk tube dried by an oven, adding a substrate (0.2 mmol, β -ketoester or malonate, 1.0 equivalent) to dissolve in 2.0mL fluorobenzene, cooling to 0 ℃, adding NaH (0.44 mmol, 2.2 equivalents) to stir at the temperature for 20 minutes, naturally raising the temperature to room temperature, adding difluoromethylation reagent 1 to stir at room temperature for 20 minutes, quenching with saturated aqueous ammonium chloride solution, extracting with ethyl acetate for 3 times, combining extraction phases, washing with brine once, drying an organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying a crude product by silica gel column chromatography to obtain a pure difluoromethyl functionalized product.

Example 38 following the procedure of the general formula, using difluoromethyl reagent 1a, the compound of the formula:

methyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Methyl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3ba).

The C/O ratio was 91: 9 as determined by fluorimetry, the isolated yield was 80% and the product was a yellow liquid. 1H NMR (400Hz, CDCl3) δ 7.78(d, J ═ 7.7Hz, 1H), 7.67(t, J ═ 7.4Hz, 1H), 7.56(d, J ═ 7.7Hz, 1H), 7.42(t, J ═ 7.5Hz, 1H), 6.60(t, J ═ 55.2Hz, 1H), 3.79(s, 3H), 3.72(d, J ═ 17.6Hz, 1H), 3.56(d, J ═ 17.6Hz, 1H), 19 Hz (mr (376MHz, CDCl3) δ -126.5(dd, J ═ 287.5, 54.9Hz, 1H), -129.8(dd, J ═ 287.5, 54.9, 1H), ms: m/z 263.1(C12H10F203Na +).

Example 39 following the procedure of the general formula above, using difluoromethyl reagent 1b, the compound of the formula:

methyl-2- (difluoromethyl) -6-methyl-1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Methyl-2-(difluoromethyl)-6-methyl-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bb).

The C/O ratio was 93: 7 as determined by fluorimetry, the isolation yield was 65%, the product was a white solid, melting point 65-67 ℃.1H NMR (400MHz, CDCl3) δ 7.60-7.40(m, 3H), 6.58(t, J ═ 55.2Hz, 1H), 3.78(s, 3H), 3.66(d, J ═ 17.4Hz, 1H), 3.50(d, J ═ 17.4Hz, 1H), 2.41(s, 3H), 19F NMR (376MHz, CDCl3) δ -126.6(dd, J ═ 287.5, 55.1Hz, 1H), -129.9(dd, J ═ 287.8, 55.1Hz, 1H) ms (esi): m/z 277.1(C13H12F203Na +).

Example 40 following the procedure of the general formula above, using difluoromethyl reagent 1c, the compound of the formula:

2- (difluoromethyl) -6-methoxy-1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester

Methyl-2-(difluoromethyl)-6-methoxy-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bc).

The C/O ratio was 93: 7 as determined by fluorimetry, the isolation yield was 58% and the product was a white solid with a melting point of 77-79 ℃.1H NMR (400MHz, CDCl3) δ 7.37(d, J ═ 8.4Hz, 1H), 7.19(dd, J ═ 8.4, 2.6Hz, 1H), 7.10(d, J ═ 2.6Hz, 1H), 6.51(t, J ═ 55.2Hz, 1H), 3.76(s, 3H), 3.71(s, 3H), 3.55(d, J ═ 17.1Hz, 1H), 3.40(d, J ═ 17.1Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.5(dd, J ═ 285.0, 55.3Hz, 1H), -123.0(dd, J ═ 287.6, 55.4Hz, 1H), ms esi): m/z 293.0(C13H12F204Na +).

Example 41 following the procedure of the general formula above, using 1d as difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -6- (methylthio) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Methyl-2-(difluoromethyl)-6-(methylthio)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bd).

The c/O ratio was 91: 9 as determined by fluorimetry, the isolated yield was 63% and the product was a pale yellow solid with a melting point of 57-59 ℃.1H NMR (400MHz, CDCl3) δ 7.67-7.30(m, 3H), 6.51(t, J ═ 55.2Hz, 1H), 3.71(s, 3H), 3.58(d, J ═ 17.6Hz, 1H), 3.42(d, J ═ 17.6Hz, 1H), 2.43(s, 3H), 19F NMR (376MHz, CDCl3) δ -126.5(dd, J ═ 287.5, 55.1Hz, 1H), -129.8(dd, J ═ 287.8, 55.4Hz, 1H), 13C (101MHz, CDCl3) δ 195.2(d, J ═ 6.6Hz), 166.3(d, J ═ 12.2Hz), 150.8, 140.0, 134.8, 134.8, 115.5, 18.5J ═ 12.2Hz, 150.8, esi, 15.7.5J ═ 20.5, 15.5 Hz, 15.7.5 (dd, 15 Hz, 1H), 15.5 Hz, 15.5H), 15.5 (dd, 15.7.7H): m/z 309.0(C13H12F203SNa +). HRMS (ESI): cal cd.for C13H13F203S +: 287.0548, respectively; found: 287.0538.

example 42 following the procedure of the general formula above, using 1e as the difluoromethylating agent, the compound of the formula:

methyl-2- (difluoromethyl) -5, 6-dimethoxy-1-oxo-2, 3-dihydro-1H-indene-2-carboxylate

Methyl-2-(difluoromethyl)-5.6-dimethoxy-1-oxo-2，3-dihydro-1H-indene-2-carboxy late(3be).

The C/O ratio was 91: 9 by fluorine spectroscopy, the isolation yield was 58%, the product was a white solid, melting point 104-. 1H NMR (400MHz, CDCl3) δ 7.16(s, 1H), 6.96(s, 1H), 6.58(t, J ═ 55.3Hz, 1H), 4.00(s, 3H), 3.91(s, 3H), 3.79(s, 3H), 3.61(d, J ═ 17.3Hz, 1H), 3.45(d, J ═ 17.3Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.7(dd, J ═ 286.7, 55.5Hz, 1H), -130.2(dd, J ═ 286.8, 55.5Hz, 1H), MS (ES 1): m/z 323.1(C14H14F205Na +).

Example 43 following the procedure of the general formula above, using 1f as the difluoromethylating agent, the compound of the formula:

methyl-4-bromo-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Methyl-4-bromo-2-(difluoromethyl)-1-oxo-2，3-di hydro-1H-indene-2-carboxylate(3bf).

The C/O ratio was 90: 10 by fluorimetry, the isolation yield was 60% and the product was a yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.85(d, J ═ 6.8Hz, 1H), 7.74(d, J ═ 7.7Hz, 1H), 7.34(t, J ═ 7.8Hz, 1H), 6.59(t, J ═ 55.0Hz, 1H), 3.81(s, 3H), 3.66(d, J ═ 18.0Hz, 1H), 3.48(d, J ═ 18.0Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.3(dd, J ═ 288.6, 55.0Hz, 1H), -129.6(dd, J ═ 288.8, 55.0Hz, 1H), ms esi (esi): m/z341.0(C12H 9BrF203Na +).

Example 44 following the procedure of the general formula above, using 1g of difluoromethyl reagent, the compound of the formula:

methyl-6-bromo-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Methyl-6-bromo-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bg).

The C/O ratio was 92: 8 by fluorimetry, the isolated yield was 72% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.82(d, J ═ 2.0Hz, 1H), 7.70(dd, J ═ 8.2, 2.0Hz, 1H), 7.38(d, J ═ 8.2Hz, 1H), 6.50(t, J ═ 55.1Hz, 1H), 3.72(s, 3H), 3.59(d, J ═ 17.8Hz, 1H), 3.42(d, J ═ 17.8Hz, 1H) 19F NMR (376MHz, CDCl3) δ -126.3(dd, J ═ 288.1, 51.3Hz, 1H), -129.5(dd, J ═ 289.2, 54.0Hz, 1H) 13 mr (101MHz, CDCl3) δ 194.4(d, J ═ 7.0, 7.152, 7.65, 7.26.7, 9.26 Hz, 11.7.26 Hz, 11H), 11.26H, 11H, 11.28 Hz, 21H, 11.26 Hz, 21H, 11H, 18H: m/z 340.9(C12H9BrF203Na +). HRMS (ESI): calcd. forC12H9BrF203Na +: 340.9595, respectively; found: 340.9587.

example 45 following the procedure of the general formula above, difluoromethyl reagent for 1h, the compound of the formula:

methyl-5-chloro-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate

Methyl-5-chloro-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bh).

The C/0 ratio was 90: 10 by fluorimetry, the isolation yield was 57%, the product was a pale yellow solid with a melting point of 87-89 ℃.1H NMR (400MHz, CDCl3) δ 7.63(d, J ═ 8.2Hz, 1H), 7.49(s, 1H), 7.33(d, J ═ 8.2Hz, 1H), 6.51(t, J ═ 55.1Hz, 1H), 3.72(s, 3H), 3.63(d, J ═ 17.6Hz, 1H), 3.46(d, J ═ 17.6Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.5(dd, J ═ 289.2, 57.4Hz, 1H), -129.6(dd, J ═ 289.2, 57.4Hz, 1H), ms (esl): m/z 297.0(C12H9ClF203Na +).

Example 46 following the procedure of the general formula above, using 1i as difluoromethylating agent, the compound of the formula:

methyl-5, 7-dichloro-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate

Methyl-5，7-dichloro-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bi).

The C/O ratio was 92: 8 as determined by fluorimetry, the isolation yield was 56% and the product was a white solid with a melting point of 67-69 ℃.1H NMR (400MHz, CDCl3) δ 7.46(s, 1H), 7.39(s, 1H), 6.57(t, J ═ 55.1Hz, 2H), 3.81(s, 3H), 3.67(d, J ═ 18.0Hz, 1H), 3.49(d, J ═ 18.0Hz, 1H), 19F NMR (376MHz, CDCl3) δ -127.0(dd, J ═ 288.5, 55.5Hz, 1H), -129.4(dd, J ═ 288.8, 55.5Hz, 1H), 13C NMR (101MHz, CDCl3) δ 191.4(d, J ═ 6.7Hz), 165.8(d, J ═ 11.7Hz), 156.8, 142.8, 134.2, 130.1, 128.9, 125.2, 125.82, 1, 15.7 Hz, 29.7H), esi, 29.7 Hz, 29.7H, 15.7 Hz, 29.7 Hz, 15.7H, 15H, 15.7H, 15: m/z341.0(C12H8Cl2F203Na +). HRMS (ESI): calcd. for C12H9Cl2F203Na +: 330.9711, respectively; found: 330.9698.

example 47 following the procedure of the general formula, using 1j for difluoromethylating the reagent, the compound of the formula:

ethyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Ethyl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bj).

The C/O ratio was 94: 6 by fluorimetry, the isolated yield was 82% and the product was a yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.86-7.39(m, 4H), 6.60(t, J ═ 55.3Hz, 1H), 4.25(q, J ═ 8.0Hz, 2H), 3.72(d, J ═ 17.6Hz, 1H), 3.55(d, J ═ 17.6Hz, 1H), 1.28(t, J ═ 8.0Hz, 3H), 19F NMR (376MHz, CDCl3) δ -126.7(dd, J ═ 287.5, 55.2Hz, 1H), -129.7(dd, J ═ 287.5, 55.2Hz, 1H), ms (esi): m/z 277.1(C13H12F203Na +).

Example 48 following the procedure of the general formula above, using 1k difluoromethyl reagent, the compound of the formula:

isopropyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Isopropyl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bk).

The C/O ratio was 94: 6 by fluorimetry, the isolated yield was 67%, and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.77(d, J ═ 7.7Hz, 1H), 7.67(t, J ═ 7.5Hz, 1H), 7.56(d, J ═ 7.7Hz, 1H), 7.41(t, J ═ 7.5Hz, 1H), 6.58(t, J ═ 55.4Hz, 1H), 5.09(p, J ═ 6.3Hz, 1H), 3.71(d, J ═ 17.5Hz, 1H), 3.53(d, J ═ 17.5Hz, 1H), 1.25(dd, J ═ 10.6, 6.3Hz, 6H), 19F NMR (376MHz, CDCl3) δ -126.9 (esi, J ═ 287.5, 55.5, 1H), -129.6, 55H, 129.5 Hz, 1H), -19H): m/z291.1(C14H14F203Na +).

Example 49 following the procedure of the general formula, using 1I as the difluoromethylating agent, the compound of the formula:

benzyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Benzyl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bl).

The C/O ratio was 92: 8 as determined by fluorimetry, the isolation yield was 63%, and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 7.97-7.07(m, 9H), 6.55(t, J ═ 55.2Hz, 1H), 5.35-4.94(m, 2H), 3.66(d, J ═ 17.5Hz, 1H), 3.49(d, J ═ 17.5Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.4(dd, J ═ 288.0, 55.1Hz, 1H), -129.6(dd, J ═ 287.9, 55.7Hz, 1H) ms (esi): m/z 339.1(C18H14F203Na +).

Example 50 following the procedure of the general formula above, using 1m of difluoromethyl reagent, the compound of the formula:

allyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester

Allyl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bm).

The C/O ratio was 90: 10 by fluorimetry, the isolated yield was 62% and the product was a pale yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.95-7.37(m, 4H), 6.64(t, J ═ 55.2Hz, 1H), 5.88(ddt, J ═ 17.2, 10.9, 5.5Hz, 1H), 5.42-5.20(m, 2H), 4.71(d, J ═ 5.6Hz, 2H), 3.76(d, J ═ 17.6Hz, 1H), 3.59(d, J ═ 17.6Hz, 1H), 19F NMR (376MHz, CDCl3) δ -126.5(dd, J ═ 287.7, 55.0Hz, 1H), -129.7(dd, J ═ 287.8, 55.0Hz, 1H), ms (esi): m/z 289.1(C14H12F203Na +).

Example 51 following the procedure of the general formula above, using 1n as difluoromethylating agent, the compound of the formula:

(1r, 3r, 5r, 7r) adamantan-2-yl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate

(1r，3r，5r，7r)-Adamantan-2-yl-2-(difluoromethyl)-1-oxo-2，3-dihydro-1H-indene-2-carboxylate(3bn).

The C/O ratio was 92: 8 by fluorimetry, the isolated yield was 69% and the product was a yellow liquid. 1H NMR (400MHz, CDCl3) δ 7.99-7.34(m, 4H), 6.56(t, J ═ 55.4Hz, 1H), 3.68(d, J ═ 17.5Hz, 1H), 3.51(d, J ═ 17.4Hz, 1H), 2.18(s, 3H), 2.10(s, 6H), 1.65(s, 6H), 19F NMR (376MHz, CDCl3) δ -127.2(dd, J ═ 6, 55.2Hz, 1H), -129.3(dd, J ═ 286.6, 55.4Hz, 1H), 13C NMR (101MHz, CDCl3) δ 196.3(d, J ═ 7.5Hz), 164.4(d, J ═ 11.5Hz), 154.0, 135, 3.125, 9, 9.125, 9.83, 9, 9.83 Hz, 9.26 Hz, 9, 9.26 Hz, 9.26, 9H), 15.18H, 21H, 21, 18H, 1H, 18H: m/z 383.1(C21H22F203Na +). HRMS (ESI): calcd. for C21H23F203 +: 361.1610, respectively; found: 361.1602.

example 52 following the procedure of the general formula above, using 1o difluoromethyl reagent, the compound of the formula:

benzyl-1- (difluoromethyl) -2-oxocyclopentane carboxylate

Benzyl-1-(difluoromethyl)-2-ox℃yclopentanecarboxylate(3d).

The C/O ratio was 95: 5 by fluorimetry, the isolation yield was 56% and the product was a colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 8.11-6.97(m, 5H), 6.40(t, J ═ 55.3Hz, 1H), 5.23(s, 2H), 2.88-1.94(m, 6H), 19FNMR (376MHz, CDCl3) δ -127.1(dd, J ═ 288.2, 55.1Hz, 1H), -128.4(dd, J ═ 288.3, 55.5Hz, 1H), ms (esi): m/z291.1(C14H14F203Na +).

Example 53 following the procedure of the general formula above, using 1p as the difluoromethylating agent, the compound of the formula:

benzyl-1- (difluoromethyl) -2-oxocycloheptane carboxylate

Benzyl-1-(difluoromethyl)-2-ox℃ycloheptanecarboxylate(3e).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 85 percent, and the product is colorless oily liquid. 1HNMR (400MHz, CDCl3) δ 7.56-7.21(m, 5H), 6.44(t, J ═ 55.0Hz, 1H), 5.50-5.02(m, 2H), 2.66-2.40(m, 2H), 2.35-2.20(m, 2H), 2.03-1.46(m, 6H), 19F NMR (376MHz, CDCl3) δ -128.6(dd, J ═ 284.8, 54.7Hz, 1H), -130.3(dd, J ═ 285.0, 55.4Hz, 1H), 13C NMR (101MHz, CDCl3) δ 204.8(d, J ═ 5.0Hz), 167.0(d, J ═ 8.1Hz), 134.8, 128.7, esi.6, 128.115, 6.1, J ═ 6, J ═ 8, 15.7, 15.6, J ═ 8, 15.8, 15.7, 15.8, 15, 9.8, 15, 9.7, 15.7, 5, 5.7, 5, 25, 5.42, 5, 25, 5: m/z 319.1(C16H18F203Na +). HRMS (ESI): calcd. for C16H19F203 +: 297.1297, respectively; found: 297.1286.

example 54 following the procedure of the general formula above, using 1q as the difluoromethylating agent, the compound of the formula:

benzyl-1- (difluoromethyl) -2-oxocyclooctyl carboxylate

Benzyl-1-(difluoromethyl)-2-ox℃yclo℃tanecarboxylate(3f).

The C/O ratio was 98: 2 by fluorimetry, the isolated yield was 68% and the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.88-7.24(m, 5H), 6.42(t, J ═ 54.5Hz, 1H), 5.50-4.84(m, 2H), 2.88-2.17(m, 4H), 2.13-1.02(m, 8H), 19FNMR (MHz, CDCl3) δ -128.1(d, J ═ 55.1Hz, 1H), 13C NMR (101MHz, CDCl3) δ 208.2, 166.6(d, J ═ 4.0Hz), 134.7, 128.7, 128.6, 128.2, 115.9(t, J ═ 247.3Hz), 68.0, 66.1(t, J ═ 19.5Hz), 39.4, 28.4, 26.2, 25.9, 24.8, 24.24.esi) (esi): m/z 333.1(C17H20F203Na +). HRMS (ESI): calcd.for C17H21F203 +: 311.1453, respectively; found: 311.1443.

example 55 following the procedure of the general formula above, using 1r of difluoromethyl reagent, the compound of the formula:

2-benzoyl-3, 3-difluoro-2-methylpropionic acid methyl ester

Methyl-2-benzoyl-3，3-difluoro-2-methylpropanoate(3g).

The C/O ratio was 96: 4 by fluorimetry, the isolated yield was 60% and the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.83(dd, J-8.5, 1.2Hz, 2H), 7.57(tt, J-6.9, 1.2Hz, 1H), 7.45(t, J-7.8 Hz, 2H), 6.48(t, J-54.0, 1H), 3.75(s, 3H), 1.70(s, 3H), 19F NMR (376MHz, CDCl3) δ -127.3(dd, J-281.9, 54.6Hz, 1H), -130.3(dd, J-281.9, 55.6Hz, 1H) 13C NMR (101MHz, CDCl3) δ 193.2(d, J-6.0), 168.8(d, J-6.1), 134.7, 133.6, 6.7, 6H, 13C NMR (101MHz, CDCl3), δ 193.2(d, J-6.0 Hz), 168.8(d, J-6.1, esi, 19.7.7, 15.7.7, 7.7Hz, 7.5Hz, 7.7.5 Hz, 7.7H), 7.7H, 7.5(dd, 7.7Hz, 7.7.7.7 Hz, 7H), 7.7.7H), 7.7.7.7H, 7.7.7.7.7H, 7H: m/z 265.0(C12H12F203Na +). HRMS (ESI): calcd. for C12H13F203 +: 243.0827, respectively; found: 243.0826.

example 56 following the procedure of the general formula above, using 1s as difluoromethylating agent, the compound of the formula:

ethyl-2- (4-bromobenzyl) -2- (difluoromethyl) -3-oxobutanoate

Ethyl-2-(4-bromobenzyl)-2-(difluoromethyl)-3-oxobutanoate(3h).

The C/O ratio was 97: 3 by fluorimetry, the isolated yield was 60% and the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.42(d, J8.4 Hz, 2H), 7.04(d, J8.4 Hz, 2H), 6.06(t, J54.3 Hz, 1H), 4.50-4.04(m, 2H), 3.29(d, J5.4 Hz, 2H), 2.28(s, 3H), 1.26(t, J7.1 Hz, 3H), 19F NMR (376MHz, CDCl3) δ -125.4(dd, J283.5, 54.0Hz, 1H), -128.2(dd, J283.7, 54.2Hz, 1H), 13C NMR (101MHz, CDCl3) δ 199.0, 167.3(d, J8.6), 7.8, 6.31, 13.31, 13H), 13C NMR (101MHz, CDCl3) δ 199.0, 167.3 (dd, J8.6 Hz, 13.9.9, 18.2 Hz, 9.31, 13H), 13J 31.31.2 Hz, 18.31, 18.2 Hz, 13H), 13H, 18, 13, 18, 2, 18: m/z 366.0(C14H15BrF203Na +). HRMS (ESI): calcd. forc14h16brf203 +: 349.0245, respectively; found: 349.0240.

example 57 following the procedure of the general formula above, using 1t of difluoromethyl reagent, the compound of the formula:

ethyl-2-benzyl-2- (difluoromethyl) -3-oxobutanoic acid ester

Ethyl-2-benzyl-2-(difluoromethyl)-3-oxobutanoate(3i).

The C/O ratio was 98: 2 by fluorimetry, the isolated yield was 70% and the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.28-7.00(m, 5H), 5.96(t, J ═ 54.3Hz, 1H), 4.29-4.01(m, 2H), 3.25(s, 2H), 2.20(s, 3H), 1.15(t, J ═ 7.1Hz, 3H), 19F NMR (376MHz, CDCl3) δ -126.2(dd, J ═ 282.6, 54.8Hz, 1H), -128.6(dd, J ═ 7.5, 55.0Hz, 1H), 13C NMR (101MHz, CDCl3) δ 199.4, 167.6(d, J ═ 8.2Hz), 134.3, 130.0, 128.6, 127.5, 115.3 (esi, J ═ 358, 1.6(dd, J ═ 1.8, 1.246, 18.5Hz), dd, 2Hz, 18.7.7.7, 18.5Hz, 18.8, 18.5H), 15.7.7.7 (dd, 3Hz, 18.7.8 Hz, 18.2 Hz, 18.5Hz, 13H): m/z 293.0(C14H16F203Na +). HRMS (ESI): calcd. for C14H17F2O3 +: 271.1140, respectively; found: 271.1134.

example 58 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

ethyl-2- (difluoromethyl) -3-oxo-2- (thiophen-3-ylmethyl) butanoic acid ester

Ethyl-2-(difluoromethyl)-3-oxo-2-(thiophen-3-ylmethyl)butanoate(3j).

The C/O ratio was 99: 1 by fluorimetry, the isolated yield was 61% and the product was a pale yellow oily liquid. 1H NMR (400MHz, CDCl3) δ 7.24(dd, J-5.0, 3.0Hz, 1H), 7.03(d, J-3.0 Hz, 1H), 6.86(d, J-5.0 Hz, 1H), 6.07(t, J-54.5 Hz, 1H), 4.40-4.11(m, 2H), 3.36(s, 2H), 2.25(s, 3H), 1.25(t, J-7.1 Hz, 3H), 19F NMR (376MHz, CDCl3) δ -125.7(dd, J-283.2, 54.3Hz, 1H), -128.4(dd, J-283.2, 54.3Hz, 1H) 13C NMR (101MHz, 3) δ, 167.5 (J-2H), 19H) 13C NMR (101MHz, 19H), 19J-19H) (dd, 2Hz, 18.7H), 15.4(dd, 7.54, 19H), 19H, 18.3 Hz, 13C NMR (101MHz, 19H), 19H, 18H), 19H, 13C NMR (101MHz, 7, 18, 2H), 15, 18, 2H, 15, 2, 18, 15, 18, 2H), 13C, 18H, 15, 18, 15, 18H, 15H, 18H, 15H: m/z 299.1(C12H14F203SNa +). HRMS (ESI): calcd. for C12H15F203 +: 277.0882, respectively; found: 277.0884.

example 59 following the procedure of the general formula, using 1a for difluoromethylating the reagent, the compound of the formula:

ethyl-2- (difluoromethyl) -2- (4-methylbenzyl) -3-oxobutanoate

Ethyl-2-(difluoromethyl)-2-(4-methylbenzyl)-3-oxobutanoate(3k).

The C/O ratio was 97: 3 by fluorimetry, the isolated yield was 60% and the product was a pale yellow oily liquid. 1H NMR (400MHz, CDCl3) δ 7.10(d, J ═ 7.9Hz, 2H), 7.03(d, J ═ 7.9Hz, 2H), 6.05(t, J ═ 54.3Hz, 1H), 4.51-4.12(m, 2H), 3.32(s, 2H), 2.33(s, 3H), 2.29(s, 3H), 1.27(t, J ═ 7.1Hz, 3H), 19F NMR (376MHz, CDCl3) δ -126.5(dd, J ═ 282.3, 54.1Hz, 1H), -128.7(dd, J ═ 282.5, 54.1Hz, 1H), 13C NMR (101MHz, CDCl3) δ 199.5, 167.6(d, J ═ 8.3), 1.35, 18.35, 18.18 Hz, 18.18H), 129.18.18H, 18H, 18.35H, 18.18H, 18H, 18.35H, 18H, 18.3H, 18H, 18.3H, 18: m/z 307.10(C15H18F203Na +). HRMS (ESI): calcd. for C15H19F203 +: 285.1297, respectively; found: 282.1292.

example 60 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

benzyl-2- (difluoromethyl) -2-methyl-3-oxobutanoic acid esters

Benzyl-2-(difluoromethyl)-2-methyl-3-oxobutanoate(3l).

The C/O ratio is 97: 3, the separation yield is 60%, and the product is colorless transparent liquid. 1H NMR (400MHz, CDCl3) δ 7.71-7.12(m, 5H), 6.39(t, J ═ 55.1Hz, 1H), 5.24(s, 2H), 2.18(s, 3H), 1.56(s, 3H).19F NMR (376MHz, CDCl3) δ -127.1(dd, J ═ 285.5, 55.2Hz, 1H), -129.7(dd, J ═ 285.7, 54.8Hz, 1H) — 13C NMR (101MHz, CDCl3) δ 200.1(d, J ═ 5.4Hz), 167.3(d, J ═ 7.5Hz), 134.6, 128.7, 128.3, 114.5(t, J ═ 247.0Hz), 68.0, 63.8(t, J ═ 21.3), ms ═ 26.9, 12 Hz): m/z279.1(C13H14F203Na +). HRMS (ESI): calcd. for C13H15F203 +: 257.0984, respectively; found: 257.0979.

example 61 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

3- (difluoromethyl) -2-oxo-1-phenylindoline-3-carboxylic acid methyl ester

Methyl-3-(difluoromethyl)-2-oxo-1-phenylindoline-3-carboxylate(3m).

The C/O ratio was 96: 4 by fluorimetry, the isolation yield was 72%, the product was a pale yellow solid, m.p. 109-111 ℃. 1HNMR (400MHz, CDCl3) δ 7.70-7.30(m, 7H), 7.18(t, J ═ 7.6Hz, 1H), 6.85(d, J ═ 7.9Hz, 1H), 6.63(t, J ═ 54.8Hz, 1H), 3.82(s, 3H).19F NMR (376MHz, CDCl3) δ -127.8(dd, J ═ 55.1, 10.9Hz, 2H).13C NMR (101MHz, CDCl3) δ.4(dd, J ═ 6.1, 3.3Hz), 165.3(dd, J ═ 6.6, 3.8Hz), 145.1, 133.5, 130.3, 129.8, 128.8, 126.7, 126.0, 123.8, 121.3, 167.3, t ═ 6.6, 3.8Hz), 145.1, 133.5, 130.3, 129.8, 128.8, 126.7, 126.0, 123.8, 121.3, t ═ 2.252, 1, 1.53, 1, 23.2 Hz: m/z340.0(C17H13F2NO3Na +). HRMS (ESI): calcd.for C17H14F2NO3 +: 318.0936, respectively; found: 318.0930.

example 62 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

3- (difluoromethyl) -5-methoxy-2-oxo-1-phenylindoline-3-carboxylic acid methyl ester

Methyl-3-(difluoromethyl)-5-methoxy-2-oxo-1-phenylindoline-3-carboxylate(3n).

The C/O ratio was 92: 8 by fluorimetry, the isolation yield was 72%, the product was a blue solid with a melting point of 115-. 1H NMR (400MHz, CDCl3) δ 7.59-7.36(m, 5H), 7.08(d, J ═ 2.5Hz, 1H), 6.88(dd, J ═ 8.7, 2.5Hz, 1H), 6.78(d, J ═ 8.7Hz, 1H), 6.62(t, J ═ 54.7Hz, 1H), 3.82(s, 3H), 3.81(s, 3H), 19F NMR (376MHz, CDCl3) δ -128.0(d, J ═ 54.1Hz, 2H), 13C NMR (101MHz, CDCl3) δ 167.1(t, J ═ 5.0Hz), 165.3(t, J ═ 5.2Hz), 156.6, 138.5, 128.8, 129.8, 133.6, 115.4, 3.126, 7.122, 7.7.7, 7.7Hz, 1H), ms, 18J ═ 7.7.7 Hz, 1H, 13C NMR (d, 18 Hz): m/z 370.1(C18H15F2NO3Na +). HRMS (ESI): calcd. for C18H16F2NO3 +: 348.1042, respectively; found: 348.1033.

example 63 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

3- (difluoromethyl) -4-methyl-2-oxo-1-phenylindoline-3-carboxylic acid methyl ester

Methyl-3-(difluoromethyl)-4-methyl-2-oxo-1-phenylindoline-3-carboxylate(3o).

The C/O ratio was 95: 5 by fluorimetry, the isolation yield was 73%, the product was a white solid with a melting point of 94-96 ℃.1H NMR (400MHz, CDCl3) δ 7.56(t, J7.5 Hz, 2H), 7.47(t, J7.5 Hz, 1H), 7.42(d, J8.0 Hz, 2H), 7.26(td, J7.9, 1.6Hz, 1H), 7.02(d, J8.0 Hz, 1H), 6.68(t, J52.0 Hz, 1H), 6.68(d, J7.9 Hz, 1H), 3.86(s, 3H), 2.37(s, 3H), 19F NMR (376MHz, CDCl3) δ -122.5(dd, J282.7, 55.1Hz, 1H), -128.9(dd, J7, 54.5, 167H, 167.5H), 19H, 7, 55.1Hz, 1H), 19.9 (dd, 7, 54.7, 7, 7.5) δ -7.7.7.7, 7.7.5H, 7.7.7.7.7H, 7.23.7H, 7.7.7H, 7.7.7.7H, 7.7.7H, 7.35H, 7H, 7.7.7H, 7.7.7.7.7H, 7H, 7.7.7.7.7.7.7.55.7H, 7H, 7.7.7.35H, 7.7.7.55.7H, 7.7.7.7.55.55.7H, 7.7H, 7H, 7.55.55.55.7H, 7H, 7.55.55.5H, 7H, 7.7.7H, 7.5H: m/z 354.1(C18H15F2NO3Na +). HRMS (ESI): calcd. for C18H16F2NO3 +: 332.1093, respectively; found: 332.1086.

example 64 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

methyl-3- (difluoromethyl) -1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-3-carboxylic acid ester

Methyl-3-(difluoromethyl)-1-methyl-2-oxo-1，2，3，4-tetrahydroquinoline-3-carboxylate(3p).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 83 percent, the product is white solid, and the melting point is 119-. 1HNMR (400MHz, CDCl3) δ 7.27(d, J ═ 7.2Hz, 1H), 7.09(t, J ═ 7.5Hz, 2H), 6.99(d, J ═ 8.2Hz, 1H), 6.63(t, J ═ 55.3Hz, 1H), 3.64(s, 3H), 3.47-3.27(m, 5H), 19F NMR (376MHz, cd539cl 2) δ -127.6(dd, J ═ 281.6, 55.4), -Hz 131.9(dd, J ═ 281.4, 56.1Hz, 1H), 13C NMR (101MHz, CDCl3) δ 166.0(d, J ═ 7.8Hz), 163.5(d, J ═ 8.3), 138.2, CDCl 366, 127.9, 7.0, 7.7.7, 7.7, 18, 7.7.7, 15(dd, 18 Hz), 163.7.7.7, 7.7.7, 7.7, 15(d, J ═ 8.3.3, 18, 7.7Hz, 7.7.7.7, 15 Hz, 15: m/z 292.1(C13H13F2NO3Na +). HRMS (ESI): calcd. for C13H14F2NO3 +: 270.0936, respectively; found: 270.0929.

example 65 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

methyl-1-benzyl-3- (difluoromethyl) -2-oxo-1, 2,3, 4-tetrahydroquinoline-3-carboxylic acid ester

Methyl-1-benzyl-3-(difluoromethyl)-2-oxo-1，2，3，4-tetrahydroquinoline-3-carboxylate(3q).

The C/O ratio is more than 99: 1, the separation yield is 95 percent, the product is white solid and the melting point is 89-91 ℃ when the fluorine spectrum is detected. 1H NMR (400MHz, CDCl3) δ 7.32(dq, J23.5, 7.2Hz, 6H), 7.17(t, J7.7 Hz, 1H), 7.07(t, J7.3 Hz, 1H), 6.92(d, J8.1 Hz, 1H), 6.71(t, J55.2 Hz, 1H), 5.55(d, J16.2 Hz, 1H), 4.89(d, J16.2 Hz, 1H), 3.73(s, 3H), 3.57-3.27(m, 2H), 19F NMR (376MHz, CDCl3) δ -363 (dd, J282.0, 55.137, 1H), -131.2 (esi, J281, 6.7, 55 MHz, CDCl3) δ -367.19H, 19H (d, 19H), 19.137, 1H), -131.19H, 19H, 7.7H, 7H, 7.9H, 7H, 7.7H, 7H, 7.9H, 7: m/z368.1 (C19H17F2NO3Na +). HRMS (ESI): calcd. forC19H18F2NO3 +: 346.1249, respectively; found: 346.1242.

example 66 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2-phenylmalonic acid diethyl ester

Diethyl-2-(difluoromethyl)-2-phenylmalonate(6a).

C/O ratio of more than 99 measured by fluorine spectrum: 1, isolated in 88% yield, the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.82-7.30(m, 5H), 6.55(t, J ═ 54.9Hz, 1H), 4.35(qd, J ═ 7.1, 2.1Hz, 4H), 1.31(t, J ═ 7.1Hz, 6H), 19F NMR (376MHz, CDCl3) δ -124.1(d, J ═ 55.1Hz, 2H), ms (esi): m/z 309.1(C14H16F204Na +).

Example 67 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

diethyl-2- (4-chlorophenyl) -2- (difluoromethyl) malonate

Diethyl-2-(4-chlorophenyl)-2-(difluoromethyl)malonate(6b).

The C/0 ratio is more than 99: 1 by fluorine spectrum measurement, the isolation yield is 80 percent, and the product is light yellow oily liquid. 1H NMR (400MHz, CDCl3) δ 7.39(d, J ═ 8.8Hz, 2H), 7.30(d, J ═ 8.7Hz, 2H), 6.55(t, J ═ 54.9Hz, 1H), 4.37(qd, J ═ 7.1, 2.3Hz, 4H), 1.32(t, J ═ 7.2Hz, 6H), 19F NMR (376MHz, CDCl3) δ -124.1(d, J ═ 55.0Hz, 2H), 13C NMR (101MHz, CDCl3) δ 165.7(t, J ═ 4.6Hz), 134.9, 131.0, 128.7, 128.4, 113.8(t, J ═ 248.2Hz), 66.9(t, J ═ 21.5), 62.9 ms, 13.9): m/z 343.0(C14H15ClF204Na +). HRMS (ESI): calcd. for C14H16ClF204 +: 321.0700, respectively; found: 321.0695.

example 68 following the procedure of the general formula, using difluoromethyl reagent 1a, the compound of the formula:

diethyl-2- (difluoromethyl) -2- (4-fluorophenyl) malonate

Diethyl-2-(difluoromethyl)-2-(4-fluorophenyl)malonate(6c).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 74 percent, and the product is colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.32(dd, J-8.7, 5.1Hz, 2H), 7.08(t, J-8.7 Hz, 2H), 6.52(t, J-55.0 Hz, 1H), 4.35(qd, J-7.2, 2.4Hz, 4H), 1.30(t, J-7.1 Hz, 6H), 19F NMR (376MHz, CDCl3) δ -113.6(s, 1H), -124.2(d, J-55.0 Hz, 2H), 13C NMR (101MHz, CDCl3) 165.9(t, J-4.6 Hz), 162.8(d, J-248.6 Hz), 131.4(d, J-8.3), esi (d, J-8.126.0), δ 7.32(t, J-4.6 Hz), 21.8 (d, J-21.18 Hz), 21.18 Hz, 21 Hz: m/z 327.1(C14H15F304Na +). HRMS (ESI): calcd. for C14H16F304 +: 305.1001, respectively; found: 305.1001.

example 69 following the procedure of the general formula, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2- (4-fluorophenyl) malonic acid diethyl ester

Diethyl-2-(2，4-dichlorophenyl)-2-(difluoromethyl)malonate(6d).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 82 percent, and the product is colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.36(d, J ═ 2.2Hz, 1H), 7.32(d, J ═ 8.6Hz, 1H), 7.21(dd, J ═ 8.7, 2.2Hz, 1H), 6.74(t, J ═ 54.7Hz, 1H), 4.26(qq, J ═ 10.8, 7.1Hz, 4H), 1.22(t, J ═ 7.2Hz, 6H), 19F NMR (376MHz, CDCl3) δ -123.4(d, J ═ 54.6Hz, 2H), 13C NMR (101MHz, CDCl3) δ 165.1(t, J ═ 3.8Hz), 135.4, 135.0, 132.9, 130.7, esi.6, 127.1, 113.5, J ═ 63.5, J ═ 13.249 (t, 13.8 Hz), ms (21.8 Hz): m/z 376.9(C14H14Cl2F204Na +). HRMS (ESI): calcd. forc14h15cl2f204 +: 355.0310, respectively; found: 355.0306.

example 70 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2- (4-methoxyphenyl) malonic acid diethyl ester

Diethyl-2-(difluoromethyl)-2-(4-methoxyphenyl)malonate(6e).

The C/0 ratio was greater than 99: 1 as determined by fluorimetry, the isolated yield was 91%, and the product was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.28(d, J ═ 8.9Hz, 2H), 6.94(d, J ═ 9.0Hz, 2H), 6.54(t, J ═ 55.1Hz, 1H), 4.36(qd, J ═ 7.1, 2.0Hz, 4H), 3.83(s, 3H), 1.32(t, J ═ 7.1Hz, 6H), 19F NMR (376MHz, CDCl3) δ -124.2(d, J ═ 55.2Hz, 2H), 13C NMR (101MHz, CDCl3) δ 166.3(t, J ═ 4.5Hz), 159.7, 130.6, 122.2, 114.2(t, J ═ 247.8Hz), 113.7, 66.7(t, J ═ 62.21), 62.6.21, 13.9 Hz): m/z 339.1(C15H18F205Na +). HRMS (ESI): calcd. for C15H19F205 +: 317.1195, respectively; found: 317.1186.

example 71 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2-benzyl-2- (difluoromethyl) malonic acid diethyl ester

Diethyl-2-benzyl-2-(difluoromethyl)malonate(6f).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 91 percent, and the product is colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.43-7.19(m, 5H), 6.08(t, J ═ 54.2Hz, 1H), 4.99-3.98(m, 4H), 3.46(s, 2H), 1.27(t, J ═ 7.2Hz, 6H), 19F NMR (376MHz, CDCl3) δ -127.5(d, J ═ 54.2Hz, 2H), ms (esi): m/z323.0(C15H18F204Na +).

Example 72 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2- (4-nitrobenzyl) malonic acid diethyl ester

Diethyl-2-(difluoromethyl)-2-(4-nitrobenzyl)malonate(6g).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 72 percent, and the product is colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 8.13(d, J ═ 9.0Hz, 2H), 7.45(d, J ═ 9.0Hz, 2H), 6.20(t, J ═ 54.3Hz, 1H), 4.77-3.87(m, 4H), 3.53(s, 2H), 1.25(t, J ═ 7.1Hz, 6H), 19F NMR (376MHz, CDCl3) δ -125.7(d, J ═ 54.3Hz, 2H), 13C NMR (101MHz, CDCl3) δ 165.9(t, J ═ 4.1Hz), 147.2, 142.6, 131.5, 123.3, 114.4(t, J ═ 248.4Hz), 62.6, 62.6(t, J ═ 20.9), esi ═ 3.34, J ═ 9, 13.8 Hz), ms (13.7 Hz, 13H): m/z368.1(C15H17F2N06Na +). HRMS (ESI): calcd. for C15H18F2N06 +: 346.1097, respectively; found: 346.1091.

example 73 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2- (2-nitrobenzyl) malonic acid diethyl ester

Diethyl-2-(difluoromethyl)-2-(2-nitrobenzyl)malonate(6h).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the isolation yield is 72 percent, and the product is light yellow oily liquid. 1H NMR (400MHz, CDCl3) δ 7.92(d, J ═ 8.0Hz, 1H), 7.60(d, J ═ 8.0Hz, 1H), 7.53(t, J ═ 7.6Hz, 1H), 7.42(t, J ═ 7.7Hz, 1H), 6.26(t, J ═ 54.4Hz, 1H), 4.30-4.06(m, 4H), 3.86(s, 2H), 1.18(t, J ═ 7.2, 6H), 19FNMR (376MHz, CDCl3) δ -126.4(d, J ═ 54.6Hz, 2H), 13C NMR (101MHz, CDCl3) δ 165.9(t, J ═ 4.0Hz), 150.4, 133.8, 132.6, 130.3, 130.6 Hz, 13H), 13C NMR (101MHz, CDCl3) δ 165.9(t, J ═ 4.0Hz, 150.8, 15, 15.9, 13.5 Hz, 13J ═ 20 Hz, 13H), ms (t, 13.5J ═ 7.5Hz, 13H), 15, 13H), 13H, 15: m/z368.1(C15H17F 2NO6Na +). HRMS (ESI): calcd. for C15H18F2N06 +: 346.1097, respectively; found: 346.1088.

example 74 following the procedure of the general formula, using difluoromethyl reagent 1a, the compound of the formula:

1, 1-dimethyl-2- (difluoromethyl) -2- (4-methoxybenzyl) malonate

Dimethyl-2-(difluoromethyl)-2-(4-methoxybenzyl)malonate(6i).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the separation yield is 94 percent, and the product is colorless oily liquid. 1H NMR (400MHz, CDCl3) δ 7.08(d, J ═ 8.5Hz, 2H), 6.81(d, J ═ 8.5Hz, 2H), 6.02(t, J ═ 54.2Hz, 1H), 3.77(s, 9H), 3.38(s, 2H).19F NMR (376MHz, CDCl3) δ -127.7(d, J ═ 54.4Hz, 2H).13C NMR (101MHz, CDCl3) δ 166.9(t, J ═ 3.3Hz), 159.0, 131.1, 125.8, 114.4(t, J ═ 247.9Hz), 113.9, 62.5(t, J ═ 20.4Hz), 55.2, 53.0, 35.5(t, J ═ 3.2) (ms ═ 3.2): m/z 325.1(C14H16F205Na +). HRMS (ESI): calcd. for C14H17F205 +: 303.1039, respectively; found: 303.1033.

example 75 following the procedure of the general formula above, using difluoromethyl reagent 1a, the compound of the formula:

2- (difluoromethyl) -2- ((5- (ethoxycarbonyl) furan-3-yl) methyl) malonic acid diethyl ester

Diethyl-2-(difluoromethyl)-2-((5-(ethoxycarbonyl)furan-3-yl)methyl)malonate(6j).

The C/O ratio is more than 99: 1 by fluorine spectrum measurement, the isolation yield is 80 percent, and the product is light yellow oily liquid. 1H NMR (400MHz, CDCl3) δ 7.04(d, J ═ 3.4Hz, 1H), 6.27(d, J ═ 3.3Hz, 1H), 6.23(t, J ═ 54.3Hz, 1H), 4.28(dq, J ═ 9.7, 7.2Hz, 6H), 3.50(s, 2H), 1.32(t, J ═ 7.1Hz, 3H), 1.25(t, J ═ 7.1Hz, 6H), 19F NMR (376MHz, CDCl3) δ -127.3(d, J ═ 54.3Hz, 2H), 13C NMR (101MHz, CDCl3) δ 165.6(t, J ═ 3.9Hz), 158.4, 158.6, 144.2, 118.7, 114.3(t, 114.3, t, 3.248, 13.60, 13.1 Hz, 13H), 13J ═ 7.1Hz, 13H, 13C NMR (t, 13 Hz, 13H), 20.1 Hz, 13H), esi, 13.1, 13H, 1, 1.1, 13H, 1: m/z 385.1(C16H20F207Na +). HRMS (ESI): calcd. for C16H21F207 +: 363.1250, respectively; found: 363.1239.

EXAMPLE 76 optimization of Synthesis reaction conditions for Compound 3aa

[a] Reaction conditions (unless otherwise specified): 2aa (0.1mmol), base, 1(1.2mmol, 1.2 equiv.), solvent (e.g., fluorobenzene, 1.0mL), room temperature, 20 min. The yield and the ratio of 3aa/4aa were quantified by fluorimetry. [b] The reaction temperature was 0 ℃. [c] The yields of isolated product are given in parentheses.

Example 772- (difluoromethyl) -2- (hydroxymethyl) -1,2,3, 4-tetrahydronaphthalen-1-ol

Preparation of 2- (Difluoromethyl) -2- (hydroxymethy) -1,2,3, 4-tetrahydronaphtalen-1-ol (7)

3aa (46.3mg, 0.18mmol, in 1mL THF) was slowly added dropwise to a mixture of lithium aluminum hydride and anhydrous Tetrahydrofuran (THF) at 0 deg.C under nitrogen, and the reaction was maintained at this temperature for 1 hour. Excess lithium aluminum hydride was quenched carefully dropwise with ethyl acetate and then 10% hydrochloric acid solution was added. After stirring for 20 min, it was extracted with ethyl acetate (20mL x 3). And combining organic phases, washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and performing rotary drying under reduced pressure. Column chromatography (300-mesh 400-mesh silica gel, n-hexane: ethyl acetate 5: 1) was performed to separate and purify two diastereomers 7(30.0mg, 72%, dr 5: 1).

Wherein the less polar compound is a white solid having a melting point of 111.1-112.1 deg.C.¹H NMR(400MHz，CDCl₃)：δ7.54(d，J＝7.2Hz，1H)，7.29-7.22(m，2H)，7.13(d，J＝7.2Hz，1H)，6.18(t，J＝56.4Hz，1H)，4.97(s，1H)，3.83(t，J＝12Hz，2H)，2.86-2.72(m，2H)，1.94-1.87(m，1H)，1.77-1.70(m，1H)，1.94-1.70(br，2H).¹³C NMR(CDCl₃，101MHz)δ137.2，135.7，128.4，127.9，127.3，126.8，118.1(t，J＝242.6Hz)，70.7(t，J＝4.7Hz)，63.3(t，J＝4.4Hz)，45.7，25.1，21.5(t，J＝4.0Hz).¹⁹F NMR(376MHz，CDCl₃)：δ-133.5(dd，J＝227.5，56.4Hz)，-134.9(dd，J＝227.5，56.4Hz).MS(ESI)：m/z 229(M+H⁺)；HRMS calcd for(C₁₂H₁₄F₂O₂+H⁺)：229.1035，Found：229.1038.

The more polar compound is a white solid with a melting point of 111.1-112.1℃。¹H NMR(400MHz，CDCl₃)：δ7.39(d，J＝7.0Hz，1H)，7.29-7.23(m，2H)，7.17(d，J＝7.0Hz，1H)，6.12(t，J＝56.0Hz，1H)，4.73(s，1H)，3.79(d，J＝12.4，1H)，3.65(d，J＝12.4，1H)，2.96-2.81(m，2H)，2.04-1.98(m，1H)，1.88-1.83(m，1H)，2.05-1.83(br，2H).¹³C NMR(101MHz，CDCl₃)δ136.2，135.6，129.0，128.9，128.4，126.8，120.3(dd，J＝243.4Hz，2.4Hz)，69.7(dd，J＝2.9Hz，2.5Hz)，62.2(t，J＝3.6Hz)，45.7(t，J＝16.7Hz)，24.7，20.4(dd，J＝3.6Hz，2.0Hz).¹⁹F NMR(376MHz，CDCl₃)：δ-129.0(dd，J＝228.6，55.3Hz)，-133.4(dd，J＝228.6，55.3Hz).MS(ESI)：m/z 251(M+Na⁺)；HRMS(ESI)：calcd for(C₁₂H₁₄F₂O₂+Na⁺)：251.0854，Found：251.0849.

Example 78 methyl-2- (difluoromethyl) -1,2,3, 4-tetrahydronaphthalene-2-carboxylate

Preparation of Methyl-2- (Difluoromethyl) -1,2,3, 4-tetrahydronaphthalene-2-carboxylate (8)

3aa (30 mg, 0.12 mmol) was dissolved in 1.0mL of trifluoroacetic acid, 0.1mL (0.63 mmol) of triethylsilane was added dropwise to the above solution at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 2 hours; heating to room temperature and stirring overnight; then cooled to 0 ℃, quenched with aqueous sodium bicarbonate, extracted 3 times with ethyl acetate, the organic phase washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by silica gel column chromatography (n-hexane/ethyl acetate 100: 1) to give 21.2 mg of compound 8 in 75% yield as a colorless liquid.

1H NMR(400MHz，CDCl3)：δ7.17-7.14(m，3H)，7.08-7.06(m，3H)，6.00(t，J＝44.8Hz，1H)，3.70(s，3H)，3.28(d，J＝13.2Hz，1H)，3.01(d，J＝13.2Hz，1H)，2.88-2.75(m，2H)，2.30-2.45(m，1H)，1.97-1.91(m，1H).13C NMR(101MHz，CDCl3)δ171.8，134.9，133.4，129.2，128.6，126.3，126.2，117.6(t，JC-F＝196.8Hz)，52.8，51.0(t，JC-F＝15.5Hz)，29.3(t，JC-F＝3.0Hz)，25.9，25.6(dd，JC-F＝2.1Hz，1.4Hz).19F NMR(376MHz，CDCl3)：δ-127.8(dd，J＝227.8，55.0Hz)，-132.3(dd，J＝227.8，55.0Hz).MS(ESI)：m/z 241(M+H+)；HRMS(ESI)calcd for(C13H14F202+H+)：241.1035，Found：241.1032.

Example 793 a- (difluoromethyl) -2, 3a, 4, 5-tetrahydro-3H-benzo [ g ] indazol-3-one

Preparation of 3a- (difluoromethyl) -2, 3a, 4, 5-tetrahydro-3H-benzol [ g ] indazol-3-one (9)

Hydrazine hydrate (0.6mmol) was added to a solution of 3aa (51.0mg, 0.2mmol) in ethanol (5mL) and heated at reflux for 15 min. The solvent was evaporated under reduced pressure, ethyl acetate was added to dissolve the organic phase, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. The crude product was isolated and purified by column chromatography (300-400 mesh silica gel, n-hexane: ethyl acetate 2: 1) to give product 9(35.0mg, 75%) as a white solid, mp 189-191 ℃.1H NMR (500MHz, DMSO-d6) δ 11.78(s, 1H), 7.72(dd, J-7.6, 1.4Hz, 1H), 7.41(td, J-7.5, 1.4Hz, 1H), 7.32(t, J-8.2 Hz, 2H), 6.41(t, J-54.0 Hz, 1H), 3.14(ddd, J-18.4, 12.8, 5.8Hz, 1H), 2.94(dd, J-17.9, 6.4Hz, 1H), 2.43(dd, J-13.9, 5.1Hz, 1H), 2.08-1.97(m, 1H), 19F NMR (376MHz, esi-d 6) δ -78 (d, J-284, 5.1Hz, 1H), DMSO (7.55, 7.31 Hz, 7.31, 19H), DMSO, 3, 19H, 3.26, 26, 19H, 3.55, 26, 3.55, 19H), 3.55, 26, 3.55, 26, 3.8Hz, 3.38, 3.8, 3, 3.8Hz, 3.38, 3, 3.8, 3, 19H, 3, 19H, 3, 27, 3, 19H, 3: m/z 273.1(C12H11F2N20+). HRMS (ESI): calcd. for C12H11F2N20 +: 273.0828, respectively; found: 273.0834.

the foregoing examples are partially referenced (note: references herein are references in the examples and product characterization)

[1](a)B.R.Langlois，J.Fluorine Chem.1988，41，247-262.(b)G.K.S.Prakash，C.Weber，S.Chacko，G.A.Olah，Org.Lett.2007，9，1863-1866.(c)J.Walkowiak-Kulikowska，J.Kanigowska，H.Koroniak，J.Fluorine Chem，2015，179，175-178.

[2]Y.Zafrani，G.Sod-Moriah，Y.Segall，Tetrahedron 2009，5278-5283.

[3](a)Q.-H.Deng，H.Wadephl，L.H.Gade，J.Am.Chem.S℃.2012，134，10769-10772；(b)I.Gebel，J.Christoffers，Eur.J.Org.Chem.2016918-920；(c)R.A.Craig II，J.L.Roizen，R.C.Smith，A.C.Jones，B.M.Stoltz，Org.Lett.，2012，14，5716-5719；(d)L.-Q.Cui，Z.-L.Dong，K.Liu，C.Zhang，Org.Lett.2011，13，6488-6491；(e)X.Wang，G.-K.Liu，X.-H.Xu，N.Shibata，N.Tokunaga，N.Shibata，Angew.Chem.Int.Ed.2014，53，1827-1831；(f)J.-J.Jiang，J.Huang，D.Wang，Z.-L.Yuan，M.-X.Zhao，F.-J.Wang，M.Shi，Chirality2011，23，272-276；(g)X.Gu，Y.Zhang，Z.-J.Xu，C.-M.Che，Chem.Commun.2014，50，7870-7873.(h)G.-Q.Chen，B.-J.Lin，J.-M.Huang，L.-Y.Zhao，Q.-S.Chen，S.-P.Jia，Q.Yin，X.Zhang，J.Am.Chem.S℃.2018，140，8064-8068.

[4](a)X.Xie，G.Cai，D.Ma，Org.Lett.2005，7，4693-4695；(b)M.A.Aramendía，V.Borau，C.Jiménez，J.M.Marinas，J.R.Ruiz，F.J.Urbano，Tetrahedron Lett.2002，2847-2849；(c)D.L.Musso et al.J.Med.Chem.2003，46，399-408.(d)R.A.Ward etal.J.Med.Chem.2012，55，3285-3306.

[5]G.-k.Liu，X.Wang，X.Lu，X.-Hua.Xu，E.Tokunaga，N.Shibata，ChemistryOpen，2012，1，227-231.

[6]Chinese Academy Of Sciences Shanghai Organic Chemistry lnstitute；Q.-L.Shen，J.-Sh.Zhu，Y.-F.Liu-CN107235878，2017，A.

[7]K.Manuel，C.Tanja，B.michael，H.Paul，G.Bernhard，Kappe，C.Oliver，GreenChenmistry，2018，20，108-112.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A difluoromethylating agent characterized by having a salt of the following formula (I), (II) or (III),

wherein R is₁Is hydrogen, halogen, nitro, cyano, polyfluoroalkyl, C mono-or polysubstituted in the ortho-, meta-or para-position_1-20Alkyl of (C)_1-20Alkoxy or C_1-20One or more alkylthio groups; r₂Is C mono-or polysubstituted in ortho-, meta-or para-position_1-20Alkoxy group of (C)_1-20Alkylthio of, C_3-12Cycloalkoxy or C of_3-12One or more of the cycloalkylthio groups of (a);

the R is₂O or S and CF in (1)₂H in H forms an intramolecular hydrogen bond;

the salt of the difluoromethylation reagent is a sulfonium salt, and the anion of the sulfonium salt is resistant to anions

Is tetrafluoroborate or hexafluorophosphate or trifluoromethanesulfonate or fluorine, chlorine, bromine, iodine or phosphate.

2. Difluoromethylating agent according to claim 1, characterized in that it is in particular selected from:

3. a method for the preparation of a difluoromethylating agent according to any of claims 1-2, comprising the following synthetic route:

the reaction of the synthetic route is carried out under the action of trifluoromethanesulfonic anhydride, and the selected solvent is one or more of diethyl ether, n-hexane, cyclohexane, dichloromethane, chloroform, toluene or tetrahydrofuran; the reaction temperature is between 80 ℃ below zero and room temperature; the aqueous solution of the salt is an aqueous solution of sodium tetrafluoroborate and/or potassium hexafluoroborate and/or potassium hexafluorophosphate and/or sodium chloride and/or potassium fluoride and/or potassium iodide and/or sodium phosphate.

4. The method of preparing a difluoromethylating agent as claimed in claim 3, comprising: will be provided with

And the substituent is R₂Dissolving benzene in dry ether, and dropwise adding trifluoromethanesulfonic anhydride at-20-25 ℃ under stirring and nitrogen protection; after the reaction is finished, stopping stirring, standing, pouring out the ether phase at the upper layer, adding ether, continuously stirring, standing, pouring out the ether phase, and repeating the operation for more than 2 times; separating out solid, filtering, washing the filtered solid with ether, drying to obtain trifluoromethanesulfonic sulfonium salt, dissolving the salt in organic solvent, and ion-exchanging with aqueous solution of salt to obtain corresponding sulfonium salt.

5. A process for the preparation of a compound by difluoromethylation, which process comprises the following scheme, wherein 1 is the difluoromethylating agent of any one of claims 1-2:

in the route, the base is NaH, KH, LiH, CaH₂、NaOH、KOH、LiOH、CsOH、Na₂CO₃、K₂CO₃、Cs₂CO₃、K₃PO₄Or Na₃PO₄One or a combination of several of them;

the solvent is one or a combination of more of tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, benzene, toluene, xylene, chlorobenzene, fluorobenzene or bromobenzene;

the reaction temperature is-80 ℃ to 100 ℃;

wherein 3 is one of the following compounds 3 ak-3 an, 3 bj-3 bn and 3 c-3 q, methyl-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -5-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -6-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -7-methoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -3-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -6, 7-dimethoxy-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -5, 7-dimethyl-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-6-bromo-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -6-fluoro-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate, methyl-2- (difluoromethyl) -7-fluoro-1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid ester, methyl-7-chloro-2- (difluoromethyl) -1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid ester, methyl-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester, methyl-2- (difluoromethyl) -6-methyl-1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid ester, 2- (difluoromethyl) -6-methoxy-1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester, methyl, Methyl-2- (difluoromethyl) -6- (methylthio) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate, methyl-2- (difluoromethyl) -5, 6-dimethoxy-1-oxo-2, 3-dihydro-1H-indene-2-carboxylate, methyl-4-bromo-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate, methyl-6-bromo-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate, methyl-2- (difluoromethyl) -2-hydroxy-1H-indene-2-, One of methyl-5-chloro-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate, methyl-5, 7-dichloro-2- (difluoromethyl) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate;

wherein 6 is one of the following compounds 6a to 6 j;

6. the method of claim 5, wherein the difluoromethylation is performed by dissolving the substrate 2 or 5 in a solvent, cooling to-80-100 ℃, adding an alkali, stirring for 10 min-12 h, naturally raising to 18-30 ℃, adding the difluoromethylation reagent 1, stirring and reacting at the temperature for 10 min-3 h, quenching with a saturated ammonium chloride aqueous solution, extracting with ethyl acetate for more than 2 times, combining the extract phases, washing with water and brine, drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain the pure difluoromethyl functionalized product 3 or 6.